Cynthia M. Cely

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.

Implementation of guidelines for management of possible multidrug-resistant pneumonia in intensive care: an observational, multicentre cohort study.

BACKGROUND The American Thoracic Society and Infectious Diseases Society of America provide guidelines for management of hospital-acquired, ventilator-associated, and health-care-associated pneumonias, consisting of empirical antibiotic regimens for patients at risk for multidrug-resistant pathogens. We aimed to improve compliance with these guidelines and assess outcomes. METHODS We implemented a performance-improvement initiative in four academic medical centres in the USA with protocol-based education and prospective observation of outcomes. Patients were assessed for severity of illness and followed up until death, hospital discharge, or day 28. We included patients in intensive-care units who were at risk for multidrug-resistant pneumonia and were treated empirically. FINDINGS 303 patients at risk for multidrug-resistant pneumonia were treated empirically, and prescribed treatment was guideline compliant in 129 patients and non-compliant in 174 patients. 44 (34%) patients died before 28 days in the compliance group and 35 (20%) died in the non-compliance group. Five patients in the compliance group and seven in the non-compliance group were lost to follow-up after day 14. Kaplan-Meier estimated survival to 28 days was 65% in the compliance group and 79% in the non-compliance group (p=0·0042). This difference persisted after adjustment for severity of illness. Median length of stay and duration of mechanical ventilation did not differ between groups. Compliance failures included non-use of dual treatment for Gram-negative pathogens in 154 patients and absence of meticillin-resistant Staphylococcus aureus coverage in 24 patients. For patients in whom pathogens were subsequently identified, empirical treatment was active in 79 (81%) of 97 of patients receiving compliant therapy compared with 109 (85%) of 128 of patients receiving non-compliant therapy. INTERPRETATION Because adherence with empirical treatment was associated with increased mortality, we recommend a randomised trial be done before further implementation of these guidelines. FUNDING Pfizer, US Medical.

Factors associated with poor outcomes in patients with lupus nephritis.

The objective of this study was to identify the factors associated with important clinical outcomes in a case-control study of 213 patients with lupus nephritis. Included were 47% Hispanics, 44% African Americans and 9% Caucasians with a mean age of 28 years. Fifty-four (25%) patients reached the primary composite outcome of doubling serum creatinine, end-stage renal disease or death during a mean follow-up of 37 months. Thirty-four percent African Americans, 20% Hispanics and 10% Caucasians reached the primary composite outcome (P < 0.05). Patients reaching the composite outcome had predominantly proliferative lupus nephritis (WHO classes: 30% III, 32% IV, 18% V and 5% II, P < 0.025) with higher activity index score (7 ± 6 versus 5 ± 5, P<0.05), chronicity index (CI) score (4 ± 3 versus 2 ± 2 unit, P<0.025), higher baseline mean arterial pressure (MAP) (111 ± 21 versus 102 ± 14 mmHg, P<0.025) and serum creatinine (1.9 ± 1.3 versus 1.3 ± 1.0 mg/dL, P<0.025), but lower baseline hematocrit (29 ± 6 versus 31 + 5%, P<0.025) and complement C3 (54 ± 26 versus 65 + 33 mg/dL, P<0.025) compared to controls. More patients reaching the composite outcome had nephrotic range proteinuria compared to controls (74% versus 56%, P<0.025). By multivariate analysis, CI (hazard ratio [95% CI] 1.18 [1.07-1.30] per point), MAP (HR 1.02 [1.00-1.03] per mmHg), and baseline serum creatinine (HR 1.26 [1.04-1.54] per mg/dL) were independently associated with the composite outcome. We concluded that hypertension and elevated serum creatinine at the time of the kidney biopsy as well as a high CI are associated with an increased the risk for chronic renal failure or death in patients with lupus nephritis.

Incidence of Nephrotoxicity and Association With Vancomycin Use in Intensive Care Unit Patients With Pneumonia: Retrospective Analysis of the IMPACT-HAP Database

BACKGROUND The 2005 guidelines from the American Thoracic Society and the Infectious Diseases Society of America recommend vancomycin trough levels of 15 to 20 mg/L for the therapy of hospital-acquired (HAP), ventilator-associated (VAP), and health care-associated (HCAP) pneumonia. OBJECTIVE The goal of this article was to report the incidence of nephrotoxicity and associated risk factors in intensive care unit patients who received vancomycin for the treatment of HAP, VAP, and HCAP. METHODS This was a retrospective analysis of data from a multicenter, observational study of pneumonia patients. Antibiotic-associated nephrotoxicity was defined as either an increase in serum creatinine ≥0.5 mg/dL or 50% above baseline, from initiation of vancomycin to 72 hours after completion of therapy. Univariate and multivariate logistic regression analyses were performed to identify risk factors for development of renal dysfunction. RESULTS Of the 449 patients in the database, 240 received at least one dose of vancomycin and 188 had sufficient data for analysis. In these 188 patients, 63% were male. Mean (SD) age was 58.5 (17.2) years, and the mean Acute Physiology and Chronic Health Evaluation II score was 19.4 (6.4). Nephrotoxicity occurred in 29 of 188 (15.4%) vancomycin-treated patients. In multivariate analysis, initial vancomycin trough levels ≥15 mg/L (odds ratio [OR], 5.2 [95% CI, 1.9-13.9]; P = 0.001), concomitant aminoglycoside use (OR, 2.67 [95% CI, 1.09-6.54]; P = 0.03), and duration of vancomycin therapy (OR for each additional treatment day, 1.12 [95% CI, 1.02-1.23]; P = 0.02) were independently associated with nephrotoxicity. The incidence of nephrotoxicity increased as a function of the initial vancomycin trough level, rising from 7% at a trough <10 mg/L to 34% at >20 mg/L (P = 0.001). The mean time to nephrotoxicity decreased from 8.8 days at vancomycin trough levels <15 mg/L to 7.4 days at >20 mg/L (Kaplan-Meier analysis, P = 0.0003). CONCLUSIONS Nephrotoxicity may be common among intensive care unit patients with pneumonia treated with broad-spectrum antibiotic therapy that includes vancomycin. The finding that an initial vancomycin trough level ≥15 mg/L may be an independent risk factor for nephrotoxicity highlights the need for additional studies to assess current recommendations for vancomycin dosing for ICU patients with pneumonia.

Accuracy of plasma neutrophil gelatinase-associated lipocalin in the early diagnosis of contrast-induced acute kidney injury in critical illness

Purpose Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for acute kidney injury (AKI). We evaluated the diagnostic and prognostic accuracies of plasma NGAL (pNGAL) for contrast-induced AKI (CI-AKI) in critically ill patients.

Risk of contrast induced nephropathy in the critically ill: a prospective, case matched study

IntroductionComputerized tomography is frequently employed in the critically ill, often using intravenous radiocontrast material. Many of these patients have clinical features that are considered risk factors for contrast induced nephropathy, but are simultaneously at risk for renal injury from other factors related to their acute illnesses. The attributable risk for renal dysfunction from radiocontrast exposure has not been well quantified in this population.MethodsA prospective matched cohort study was conducted of patients scanned with or without radiocontrast enhancement while receiving intensive care in a Veterans Affairs Medical Center. Patients were matched for pre-scan measured creatinine clearance, diabetes, mechanical ventilation, and vasopressor use. Measured clearance was followed for three days after scanning. Evolution of nephropathy, as determined by change in measured clearance, was compared within matched pairs.ResultsFifty-three pairs of patients satisfied matching criteria. Unmatched characteristics were similar among the pairs, including serum creatinine variability during the week preceding scanning (67 ± 85% among contrast recipients, 63 ± 62% among others) and clinical risk factors for renal failure. In 29 pairs, pre-scan measured clearances were less than 60 mL/minute/1.73 m2. Following scanning, measured clearance declined by at least 33% in 14 contrast and 19 non-contrast patients (95% confidence interval for contrast associated difference in nephropathy rates -27% to 9%), while a 50% reduction in clearance persisted three days after scanning in three contrast and nine non-contrast patients (95% confidence interval for difference in rates -25% to 2%).ConclusionsAmong established intensive care unit patients declines in glomerular filtration following contrast-enhanced scanning are common, but these changes are far more likely to be attributable to factors other than the contrast exposure itself. The upper bound for the incidence of contrast induced renal injury lasting even three days was 2% in the population studied.

Acute Lung Injury Outside of the ICU : Incidence in Respiratory Isolation on a General Ward

BACKGROUND Epidemiologic investigations of acute lung injury (ALI) and ARDS have focused on mechanically ventilated patients in ICUs, and have reported high mortality rates. We sought to determine the incidence and lethality of these syndromes in the respiratory isolation areas of general wards, a non-ICU setting that often serves patients with acute lung processes. METHODS We prospectively studied all patients who were admitted to respiratory isolation rooms on the general wards of a large tertiary care hospital over a 1-year period. Patients were classified as having ALI or ARDS if they met consensus definitions for the syndromes. Characteristics and outcomes were compared to those of other patients who had been admitted to a respiratory isolation room with infiltrating lung disease but lacking bilateral infiltrates, hypoxemia, or both. RESULTS Of 715 patients admitted to respiratory isolation rooms on general wards, 474 (66%) had acute infiltrates. ALI criteria were met by 9% of patients (62 of 715 patients), with 2% of patients (15 of 715) satisfying the criteria for ARDS. Respiratory distress was present in 71% of ALI patients (44 of 62 patients) and 32% of patients (130 of 412 patients) with acute infiltrates who did not have ALI (p < 0.001). However, the 90-day survival rates (ALI patients, 88%; patients with acute infiltrates who did not have ALI, 90%) was similar between the two groups (p > 0.50). CONCLUSIONS ALI and ARDS may be frequent among patients who are admitted to respiratory isolation beds outside of ICUs. Mortality rates are substantially lower than those typically reported from surveys of ventilated ICU patients with ALI and ARDS.

Pseudo Sister Mary Joseph's nodule

The Sister Mary Josephs nodule is a significant finding in the physical examination. It is sometimes the only indication of an intra-abdominal metastatic malignancy. We report a patient who presented with an umbilical nodule that was discovered to be an omphalith. A review of the literature discusses the Sister Mary Josephs nodule and this unusual finding.

Use of intensive care, mechanical ventilation, both, or neither by patients with acute lung injury.

Objective:Reports of acute lung injury and acute respiratory distress syndrome have generally been restricted to mechanically ventilated intensive care unit patients, creating an incomplete picture of the epidemiologies of the syndromes. We sought to determine the incidence and outcomes of acute lung injury and acute respiratory distress syndromes throughout an entire hospital population. Design:Retrospective cohort study. Setting:A Department of Veterans Affairs medical center. Patients:All patients satisfying criteria for acute lung injury or acute respiratory distress syndrome during a 2-yr period. Interventions:None. Measurements and Main Results:There were 11,465 acute medical and surgical admissions during the study period; 156 patients had acute lung injury or acute respiratory distress syndrome. Only 74 (47%) were invasively ventilated in an intensive care unit for acute lung injury. Another 15 (10%) patients were ventilated for other reasons, 41 (26%) were admitted to an intensive care unit at approximately the time of acute lung injury onset but were not invasively ventilated, and 26 (17%) were managed with neither invasive ventilation nor admission to an intensive care unit. Four-week mortality differed by group (p = .023), ranging from 22% among those managed in an intensive care unit without invasive ventilation to 50% among those ventilated for acute lung injury or acute respiratory distress syndrome. By 2 yrs, differences in survival between groups were no longer significant. Notably, only 53 (34%) patients would have been eligible for widely cited acute lung injury intervention trials. Ten patients had a second episode of acute lung injury during the study period, equating to a 16%-per-year risk of recurrence. Conclusions:Acute lung injury and acute respiratory distress syndrome studies restricted to patients mechanically ventilated in intensive care units substantially underestimate the incidence of the syndromes. Nonventilated patients and those cared for outside of intensive care units may still be at substantial risk for death. Further characterization of previously overlooked acute lung injury and acute respiratory distress syndrome patients may suggest new therapeutic opportunities.

Contrast-associated acute kidney injury in the critically ill: systematic review and Bayesian meta-analysis

Purpose Critically ill patients, among whom acute kidney injury is common, are often considered particularly vulnerable to iodinated contrast medium nephrotoxicity. However, the attributable incidence remains uncertain given the paucity of observational studies including a control group. This study assessed acute kidney injury incidence attributable to iodinated contrast media in critically ill patients based on new data accounting for sample and effect size and including a control group.MethodsSystematic review of studies measuring incidence of acute kidney injury in critically ill patients following contrast medium exposure compared to matched unexposed patients. Patient-level meta-analysis implementing a Bayesian nested mixed effects multiple logistic regression model.ResultsTen studies were identified; only four took into account the baseline acute kidney injury risk, three by patient matching (560 patients). Objective meta-analysis of these three studies (vague and impartial a priori hypothesis concerning attributable acute kidney injury risk) did not find that iodinated contrast media increased the incidence of acute kidney injury (odds ratio 0.95, 95% highest posterior density interval 0.45–1.62). Bayesian analysis demonstrated that, to conclude in favor of a statistically significant incidence of acute kidney injury attributable to contrast media despite this observed lack of association, one’s a priori belief would have to be very strongly biased, assigning to previous uncontrolled reports 3–12 times the weight of evidence strength provided by the matched studies including a control group.ConclusionsMeta-analysis of matched cohort studies of iodinated contrast medium exposure does not support a significant incidence of acute kidney injury attributable to iodinated contrast media in critically ill patients.