The role of biomarkers in early identification of acute kidney injury among non-critically ill patients.

BACKGROUND: Prediction and/or early identification of acute kidney injury (AKI) and individuals at greater risk remains of great interest in clinical medicine. Acute kidney injury continues to be a common complication among hospitalized patients, with an incidence ranging from 6 to 58%, depending on the setting. Aim of this study was to determine the performance of Insulin-like growth factor binding protein-7 (IGFBP7), tissue metallopeptidase inhibitor 2 (TIMP2), and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in early detection of AKI among non-critically ill patients. METHODS: In this prospective observational study at Mayo Clinic Hospitals in Rochester, Minnesota, USA, non-critically ill patients admitted from the emergency department between October 31st, 2016 and May 1st, 2018, who had an acute kidney injury (AKI) probability of 5% or higher were included. Biomarkers were measured in residual urine samples collected in the emergency department. The primary outcome was biomarker performance in predicting AKI development within the first 72 h. RESULTS: Among 368 included patients, the mean age was 79 ± 12 years, and 160 (43%) were male. Acute kidney injury occurred in 62 (17%) patients; 11.5% stage 1, 2.5% stage 2, and 3% stage 3. Twelve patients (3%) died during hospitalization and 102 (28%) within nine months after admission. The median uNGAL and IGFBP7-TIMP2 were 57 [20-236 ng/ml], and 0.3 [0.1-0.8], respectively. The C-statistic of uNGAL and IGFBP7-TIMP2 of > 0.3 and > 2.0 for AKI prediction were 0.56, 0.54, and 0.53, respectively. In a model where one point is assigned to each marker of AKI (elevated serum creatinine, IGFBP7-TIMP2 > 0.3, and uNGAL), a higher score correlated with higher nine-month mortality [OR of 1.32 per point (95% CI 1.02-1.71)]. CONCLUSION: Among non-critically ill hospitalized patients, the performance of uNGAL and IGFBP7-TIMP2 for AKI prediction within 72 h of admission was modest. This suggests a limited role for these biomarkers in AKI risk stratification among non-critically ill patients. Key learning points What was known Acute kidney injury (AKI) is a common complication among hospitalized patients. It is associated with increased morbidity and mortality. Various clinical prediction models and biomarkers have been developed to identify patients in special populations (such as ICU and cardiac surgery) who are at risk of AKI and diagnose AKI early. This study adds The performance of the biomarkers uNGAL, TIMP-2, and IGFBP-7 in predicting AKI within 72 h of admission in non-critically ill patients was modest. However, these biomarkers were found to have a prognostic value for predicting 9-month mortality. One potential application of these biomarkers is identifying patients at higher AKI risk before exposing them to nephrotoxic agents. Potential impact This study provides evidence regarding the real-world performance of current FDA-approved biomarkers (uNGAL, TIMP-2, and IGFBP-7) for predicting acute kidney injury (AKI) within 72 h of hospital admission among noncritically ill patients. While the performance of these biomarkers for predicting short-term AKI was modest, they may have a prognostic value for predicting 9-month mortality.

Development and validation of a model to predict acute kidney injury following high-dose methotrexate in patients with lymphoma.

STUDY OBJECTIVE: To develop and validate a model for predicting acute kidney injury (AKI) after high-dose methotrexate (HDMTX) exposure. DESIGN: Retrospective analysis. SETTING: Multisite integrated health system throughout Minnesota and Wisconsin. PATIENTS: Adult patients with lymphoma who received HDMTX as a 4-h infusion. MEASUREMENTS AND MAIN RESULTS: LASSO methodology was used to identify factors available at the outset of therapy that predicted incident AKI within 7 days following HDMTX. The model was then validated in an independent cohort. The incidence of AKI within 7 days following HDMTX was 21.6% (95% confidence interval (CI) 18.4%-24.8%) in the derivation cohort (435 unique patients who received a total of 1642 doses of HDMTX) and 15.6% (95% CI 5.3%-24.8%) in the validation cohort (55 unique patients who received a total of 247 doses of HDMTX). Factors significantly associated with AKI after HDMTX in the multivariable model included age ≥ 55 years, male sex, and lower HDMTX dose number. Other factors that were not found to be significantly associated with AKI on multivariable analysis, but were included in the final model, were body surface area, Charlson Comorbidity Index, and estimated glomerular filtration rate. The c-statistic of the model was 0.72 (95% CI 0.69-0.75) in the derivation cohort and 0.72 (95% CI 0.60-0.84) in the validation cohort. CONCLUSION: This model utilizing identified sociodemographic and clinical factors is predictive of AKI following HDMTX administration in adult patients with lymphoma.

Prospective evaluation of high-dose methotrexate pharmacokinetics in adult patients with lymphoma using novel determinants of kidney function.

High-dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single-center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7-hydroxy-MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine- or cystatin C-based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2-75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8-11.3) grams. Median clearance was similar across three dosing levels at 4.5-5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFRcys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4-h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C-based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.

Prolonged exposure to continuous renal replacement therapy in patients with acute kidney injury.

BACKGROUND: Little is known about the process of deciding to discontinue continuous renal replacement therapy (CRRT) in patients with acute kidney injury (AKI) and the impact of CRRT duration on outcomes. METHODS: We report the clinical parameters of prolonged CRRT exposure and predictors of doubling of serum creatinine or need for dialysis at 90 days after CRRT with propensity score matching, including covariates that were likely to influence patients in the prolonged CRRT group. RESULTS: Among 104 survey responders, most use urine output (87%) to guide CRRT discontinuation, 24% use improvement in clinical or hemodynamic status. In the cohort study, of 854 included patients, 465 participated in the assessment of kidney recovery. Patients with prolonged CRRT had higher SOFA scores (11.9 vs. 11.2) and were more likely to be mechanically ventilated (99% vs. 84%) at CRRT initiation compared to patients without prolonged CRRT, p-value < 0.05. In multivariable logistic regression, daily urine output and cumulative fluid balance leading to CRRT discontinuation or day seven were independently associated with lower [OR 0.87 per 200 ml/day increase] and higher odds [OR 1.03 per 1-L increase] of requiring prolonged CRRT, respectively. After propensity score matching, prolonged exposure to CRRT was independently associated with increased risk of doubling serum creatinine or dialysis at 90 days, OR 3.1 (95% CI 1.23-8.3 p = 0.017). CONCLUSIONS: Resolution of critical illness and signs of kidney recovery are important factors when considering CRRT discontinuation. Prolonged CRRT exposure may be associated with less chance of kidney recovery among survivors.

Ultrasonographic Assessment of Extravascular Lung Water in Hospitalized Patients Requiring Hemodialysis: A Prospective Observational Study.

INTRODUCTION: Sonographic technologies can estimate extravascular lung water (EVLW) in hemodialysis (HD) patients. This study investigated the suitability of a handheld scanner in contrast to a portable scanner for quantifying EVLW in hospitalized patients requiring HD. METHODS: In this prospective study, 54 hospitalized HD patients were enrolled. Bedside lung ultrasound was performed within 30 min before and after dialysis using handheld (phased array transducer, 1.7-3.8 MHz) and portable (curved probe, 5-2 MHz) ultrasound devices. Eight lung zones were scanned for total B-lines number (TBLN). The maximum diameter of inferior vena cava (IVC) was measured. We performed Passing-Bablok regression, Deming regression, Bland-Altman, and logistic regression analysis. RESULTS: The 2 devices did not differ in measuring TBLN and IVC (p > 0.05), showing a high correlation (r = 0.92 and r = 0.51, respectively). Passing-Bablok regression had a slope of 1.11 and an intercept of 0 for TBLN, and the slope of Deming regression was 1.02 within the CI bands of 0.94 and 1.11 in the full cohort. TBLN was logarithmically transformed for Bland-Altman analysis, showing a bias of 0.06 (TBLN = 1.2) between devices. The slope and intercept of the Deming regression in IVC measurements were 0.77 and 0.46, respectively; Bland-Altman plot showed a bias of -0.07. Compared with predialysis, TBLN significantly (p < 0.001) decreased after dialysis, while IVC was unchanged (p = 0.16). Univariate analysis showed that cardiovascular disease (odds ratio [OR] 8.94 [2.13-61.96], p = 0.002), smoking history (OR 5.75 [1.8-20.46], p = 0.003), and right pleural effusion (OR 5.0 [1.2-25.99], p = 0.03) were strong predictors of EVLW indicated by TBLN ≥ 4. CONCLUSION: The lung and IVC findings obtained from handheld and portable ultrasound scanners are comparable and concordant. Cardiovascular disease and smoking history were strong predictors of EVLW. The use of TBLN to assess EVLW in hospitalized HD patients is feasible. Further studies are needed to determine if TBLN can help guide volume removal in HD patients.

Clinician perspectives on inpatient cystatin C utilization: A qualitative case study at Mayo Clinic.

INTRODUCTION: Serum creatinine (SCr) testing has been the mainstay of kidney function assessment for decades despite known limitations. Cystatin C (CysC) is an alternative biomarker that is generally less affected than SCr by pertinent non-renal factors in hospitalized patients, such as muscle mass. Despite its potential advantages, the adoption of CysC for inpatient care is not widespread. At one hospital with CysC testing, we demonstrated a significant rise in non-protocolized use over the last decade. This study uses qualitative methods to provide the first report of how clinicians understand, approach, and apply CysC testing in inpatient care. METHODS: Fifteen clinicians from various disciplines were interviewed about their experience with inpatient CysC testing. The semi-structured interviews were audio-recorded, transcribed verbatim, and analyzed thematically using a phenomenological approach. RESULTS: Knowledge and confidence with CysC varied greatly. Clinicians reported first learning about the test from colleagues on consulting services or multidisciplinary teams. The majority believed CysC to provide a more accurate measure of kidney function than SCr. Common scenarios for CysC ordering included medication dosing, evaluation of acute kidney injury, and a thorough evaluation of kidney function in patients with risk factors for an altered SCr. Facilitators for ordering CysC included the availability of rapid results turnaround and the automated calculation of glomerular filtration rate based on the biomarker. Barriers to use included a lack of education about CysC, and the absence of an institutional protocol for use. DISCUSSION: Clinicians at our site decided independent of institutional guidance whether and when CysC added value to patient care. While the majority of study participants indicated advantages to rapid turnaround CysC testing, its use depended not just on the features of the specific case but on clinician familiarity and personal preference. Findings from this research can guide the implementation and expansion of CysC testing.

Characteristics and Outcomes of Kidney Transplant Recipients Requiring High-Acuity Care After Transplant Surgery: A 10-Year Single-Center Study.

OBJECTIVE: To study the characteristics and outcomes of a cohort of kidney transplant recipients who required high-acuity care after transplant surgery. PATIENTS AND METHODS: All adult (aged ≥18 years) solitary kidney transplant recipients from January 1, 2007, through December 31, 2016, were screened and those who required high-acuity care within the same hospitalization were enrolled. Patient demographic and clinical data were collected from the departmental database and electronic DataMart. RESULTS: Of 1525 patients, 266 (17.4%) required high-acuity care after the kidney transplant operation: 166 (62.4%) directly from the operating room and 100 (37.6%) after an interval during the same hospitalization. Overall, 2 main indications were hypotension (n=87; 32.7%) and cardiac rhythm disturbances (n=83; 31.2%). Recipients in the direct admission group had higher medium body mass index (31.0 [interquartile range, 26.6-36.0] vs 28.0 [interquartile range, 24.3-32.4] kg/m2; P<.001) and were more likely to have undergone a concomitant procedure with the transplant surgery. Overall, in-hospital mortality was 1.9% (n=5). CONCLUSION: In contemporary practice, patients with higher body mass index are more likely to require high-acuity care immediately after kidney transplant surgery. The most common reasons are hypotension and cardiac rhythm disorders. The overall intensive care unit mortality rate of these patients is low. However, these patients are at risk for graft loss and death in the long term compared with patients who do not require intensive care unit care after transplant surgery.

Prediction of Vancomycin Levels Using Cystatin C in Overweight and Obese Patients: a Retrospective Cohort Study of Hospitalized Patients.

The use of the kidney function biomarker cystatin C (cysC) can improve the accuracy of vancomycin dosing for target trough attainment in nonobese patients. It is unknown whether cysC can also improve vancomycin target trough attainment in overweight and obese patients. We conducted a retrospective observational study of overweight or obese hospitalized adults with stable renal function administered intravenous vancomycin between January 2011 and July 2019. Linear regression models were used to predict initial steady-state vancomycin troughs using several factors, including various cysC- and serum creatinine (SCr)-based estimates of kidney function. We compared the predicted proportion of patients within the target trough range (10 to 20 mg/liter) using the derived models to that observed from usual care. Of the 200 included patients, the mean trough level was 15 ± 6.3 mg/liter. The optimal model to predict the initial trough included both cysC and SCr (R2 = 0.48) rather than either biomarker alone. This model predicted that 79% (95% confidence interval [CI], 73% to 85%) of troughs could be between 10 and 20 mg/liter compared to the 62% observed in clinical practice (P < 0.001), a 1.3-fold increase. This study is the first to examine the role of cysC in predicting vancomycin levels in an exclusively overweight or obese population. While dosing models based on cysC appear promising in this setting, prospective validation is needed.

Patterns of Cystatin C Uptake and Use Across and Within Hospitals.

OBJECTIVE: To characterize the use of cystatin C (cysC) across and within hospitals. PATIENTS AND METHODS: This 2-part study first evaluated access to cysC testing across 129 hospitals in the state of Minnesota, using a telephone-based survey. Second, granular data from a single center (Mayo Clinic) with on-site, rapid-turnaround testing (<1 day) and automated estimated glomerular filtration rate (eGFR) reporting was used to describe temporal patterns. The characteristics of hospitals that offered cysC testing and of patients who underwent rapid cysC testing at Mayo Clinic between January 1, 2011, and March 31, 2018, were described. Poisson regression analyzed temporal trends in cysC testing. RESULTS: Of the 114 hospitals (88%) that responded to the statewide survey, cysC was available in 91 (80%), but only 3 of 91 (3%) reported a turnaround time of <1 day. At Mayo Clinic, cysC use increased from 0.74 tests per 1000 patient-days in 2011 to 14 tests per 1000 patient-days in 2018 (P=.004). Of the 3774 patients with cysC tests, the mean first available eGFR was 46 mL/min per 1.73 m2 using cysC and 59 mL/min per 1.73 m2 using serum creatinine (P<.001). CysC testing was used across all intensities of care and was ordered by a variety of specialties. Nephrology was consulted in only 42% of cases. CONCLUSION: In the hospital, rapid-turnaround cysC testing is necessary for practical use but was not widely available in Minnesota. When available, a marked increase in cysC testing was observed over the study timeframe. Additional research is needed to determine optimal strategies for implementation of cysC within hospitals.

Predictors of Augmented Renal Clearance in a Heterogeneous ICU Population as Defined by Creatinine and Cystatin C.

INTRODUCTION: The incidence of augmented renal clearance (ARC) in the intensive care unit (ICU) is highly variable, and identification of these patients remains challenging. OBJECTIVE: The objective of this study was to define the incidence of ARC in a cohort of critically ill adults, using serum Cr and cystatin C, and to identify factors associated with its development. METHODS: This is a retrospective cohort study of critically ill patients without stage 2 or 3 acute kidney injury with both serum Cr and cystatin C available. The incidence of ARC was defined as a Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)Cr-cystatin C-estimated glomerular filtration rate >130 mL/min. A multivariable logistic regression model using a penalized Lasso method was fit to identify independent predictors of ARC. RESULTS: Among the 368 patients included in the study, indication for ICU admission was nonoperative in 55% of patients, and 9% of patients were admitted for major trauma. The overall incidence of ARC was low at 4.1%. In a multivariable logistic regression model, Charlson comorbidity index, major trauma, intracerebral hemorrhage, age, and Sequential Organ Failure Assessment score were found to predict ARC. CONCLUSION: The incidence of ARC in this study was low, but prediction models identified several factors for early identification of patients with risk factors for or who develop ARC, particularly in a cohort with a low baseline risk of ARC. These factors could be used to help identify patients who may develop ARC.

Risk Factors for Acute Kidney Injury in Hospitalized Non-Critically Ill Patients: A Population-Based Study.

OBJECTIVE: To develop and validate an acute kidney injury (AKI) risk prediction model for hospitalized non-critically ill patients. PATIENTS AND METHODS: We retrospectively identified all Olmsted County, Minnesota, residents admitted to non-intensive care unit (ICU) wards at Mayo Clinic Hospital, Rochester, Minnesota, in 2013 and 2014. The cohort was divided into development and validation sets by year. The primary outcome was hospital-acquired AKI defined by Kidney Disease: Improving Global Outcomes criteria. Cox regression was used to analyze mortality data. Comorbid risk factors for AKI were identified, and a multivariable model was developed and validated. RESULTS: The development and validation cohorts included 3816 and 3232 adults, respectively. Approximately 10% of patients in both cohorts had AKI, and patients with AKI had an increased risk of death (hazard ratio, 3.62; 95% CI, 2.97-4.43; P<.001). Significant univariate determinants of AKI were preexisting kidney disease, diabetes mellitus, hypertension, heart failure, vascular disease, coagulopathy, pulmonary disease, coronary artery disease, cancer, obesity, liver disease, and weight loss (all P<.05). The final multivariable model included increased baseline serum creatinine value, admission to a medical service, pulmonary disease, diabetes mellitus, kidney disease, cancer, hypertension, and vascular disease. The area under the receiver operating characteristic curves for the development and validation cohorts were 0.71 (95% CI, 0.69-0.75) and 0.75 (95% CI, 0.72-0.78), respectively. CONCLUSION: Hospital-acquired AKI is common in non-ICU inpatients and is associated with worse outcomes. Patient data at admission can be used to identify increased risk; such patients may benefit from more intensive monitoring and earlier intervention and testing with emerging biomarkers.

Prediction of the Renal Elimination of Drugs With Cystatin C vs Creatinine: A Systematic Review.

Serum cystatin C has been proposed as a kidney biomarker to inform drug dosing. We conducted a systematic review to synthesize available data for the association between serum cystatin C and drug pharmacokinetics, dosing, and clinical outcomes in adults (≥18 years). PubMed, Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL, and Scopus were systematically searched from 1946 to September 2017 to identify candidate studies. Studies of cystatin C as a predictor for acute kidney injury or for management of contrast-associated acute kidney injury were excluded. Also, studies were excluded if drug concentrations were unavailable and if a reference standard for drug dosing (eg, serum creatinine) was not concurrently reported. The outcomes of interest included drug clearance (L/h), concentrations (mg/L), target level achievement (%), therapeutic failure (%), and drug toxicity (%). We included 28 articles that evaluated 16 different medications in 3455 participants. Vancomycin was the most well-studied drug. Overall, cystatin C-based estimated glomerular filtration rate (eGFRCystatin C) was more predictive of drug levels and drug clearance than eGFRCreatinine. In only one study were target attainment and outcomes compared between 2 drug-dosing regimens, one based on eGFRCreatinine-Cystatin C and one dosed with the Cockcroft-Gault creatinine clearance equation. Compared with eGFRCreatinine, use of eGFRCystatin C to predict elimination of medications via the kidney was as accurate, if not superior, in most studies, but infrequently were data on target attainment or clinical outcomes reported. Drug-specific dosing protocols that use cystatin C to estimate kidney function should be tested for clinical application.

Validation of the sarcopenia index to assess muscle mass in the critically ill: A novel application of kidney function markers.

BACKGROUND & AIMS: Adverse outcomes for hospitalized patients with sarcopenia are well documented, and identification of patients at risk remains challenging. The sarcopenia index (SI), previously defined as (serum creatinine/serum cystatin C) × 100, could be an inexpensive, readily accessible, objective tool to predict muscle mass and risk for adverse clinical outcomes. The aim of this study was to assess the validity of the SI as a predictor of muscle mass. METHODS: Retrospective study of critically ill adults admitted to Mayo Clinic from 2012 to 2015 with suspected sepsis and an available creatinine and serum cystatin C. Muscle surface area was quantified at the L3/4 vertebral level in patients with an abdominal CT scan (CTMSA). Multivariable regression modeling was used to assess the relationship between SI and CTMSA, as well as short-term clinical outcomes. RESULTS: The 171 included had a mean weight and body mass index (BMI) of 75.2 ± 16.4 kg and 26.0 ± 4.6 kg/m2 and abdominal CT scans were available for 81 (47%) patients. The SI correlated with CTMSA (r = 0.40). After adjustment for age, sex, severity of illness, and BMI, SI was independently associated with muscle mass (P = 0.001). A decrease in the SI (indicative of lower muscle mass) was also associated with frailty and worse short-term clinical outcomes. CONCLUSION: The SI, a simple calculation from kidney function markers, is a significant predictor of muscle mass in this validation cohort of ICU patients. A low SI was associated with longer hospital length of stay and frailty. Future studies could explore whether the use of SI assists with identifying patients likely to benefit from pharmacotherapy-, nutrition-, or physical therapy-based interventions.

Sarcopenia Index Is a Simple Objective Screening Tool for Malnutrition in the Critically Ill.

BACKGROUND: Reliable and valid tools to screen for malnutrition in the intensive care unit (ICU) remain elusive. The sarcopenia index (SI) [(serum creatinine/serum cystatin C) × 100], could be an inexpensive, objective tool to predict malnutrition. We evaluated the SI as a screening tool for malnutrition in the ICU and compared it with the modified-NUTRIC score. MATERIALS AND METHODS: This was a historical cohort study of ICU patients with stable kidney function admitted to Mayo Clinic ICUs between 2008 and 2015. Malnutrition was defined by the Subjective Global Assessment. Diagnostic performance was evaluated with the area under the receiver operating characteristic curve (AUC) and multivariable logistic regression. RESULTS: Of the 398 included patients, 181 (45%) had malnutrition, with 34 (9%) scored as severely malnourished. The SI was significantly lower in malnourished patients than in well-nourished patients (64 ± 27 vs 72 ± 25; P = 0.002), and reductions in SI corresponded to increased malnutrition severity (P = 0.001). As a screening tool, the SI was an indicator of malnutrition risk (AUC 0.61) and performed slightly better than the more complex modified-NUTRIC score (AUC = 0.57). SI cutoffs of 101 and 43 had >90% sensitivity and >90% specificity, respectively, for the prediction of malnutrition. Patients with a low SI (≤43) had a significantly higher risk of mortality (HR = 2.61, 95% CI 1.06-6.48, P = 0.038). CONCLUSION: The frequency of malnutrition was high in this critically ill population, and it was associated with a poor prognosis. The SI could be used to assess nutrition risk in ICU patients.

Impact of Serum Cystatin C-Based Glomerular Filtration Rate Estimates on Drug Dose Selection in Hospitalized Patients.

STUDY OBJECTIVE: Serum creatinine (Scr ) concentration is used to calculate estimated glomerular filtration rate (eGFR) for medication dosing. Serum cystatin C (CysC) concentration has been proposed as an adjunct or alternative to Scr . This study sought to evaluate the possible impact of using CysC in eGFR equations on drug dose recommendations in hospitalized patients with infections. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Large academic tertiary care medical center. PATIENTS: A total of 308 adults with suspected or documented infections and stable kidney function who were hospitalized between 2012 and 2015. MEASUREMENTS AND MAIN RESULTS: Standardized Scr and CysC measured at the time of antibiotic dosing were used to estimate GFR from the three Chronic Kidney Disease Epidemiology Collaborative (CKD-EPI) equations using Scr (eGFRCr ), CysC(eGFRCysC ), or a combination of Scr and CysC (eGFRCr-CysC ), and these values were compared with estimated creatinine clearance (eClcr ) from the Cockcroft-Gault equation (standard of care for drug dosage adjustments). The eGFRs were categorized into five common dosage adjustment strata (lower than 20, 20-49, 50-79, 80-130, and higher than 130 ml/min), and agreement between equations was tested with the weighted κ statistic. Recommended drug doses varied considerably between the eClcr and the CKD-EPI equations (weighted κ [95% confidence interval]: eGFRCr 0.73 [0.68-0.79], eGFRCysC 0.42 [0.35-0.5], eGFRCr-CysC 0.65 [0.6-0.71]). If eGFRCr, eGFRCysC , or eGFRCr-CysC were used instead of eClcr to dose drugs, 11%, 12%, and 8% of doses, respectively, would be higher, and 12%, 38%, and 24% of doses, respectively, would be lower. CONCLUSION: Significant discordance in drug doses was observed when the CKD-EPI equations were used in place of eClcr . When CysC was included in eGFR equations, recommended doses were often lower. Further study is needed to develop and test drug-specific dosing guidelines that incorporate alternate renal biomarkers and/or more contemporary eGFR equations.

Features of Adult Hyperammonemia Not Due to Liver Failure in the ICU.

OBJECTIVES: To evaluate the epidemiology of hyperammonemia unrelated to liver failure in the critical care setting. DESIGN: Retrospective case series. SETTING: Critically ill patients admitted to ICUs at Mayo Clinic, Rochester, MN (medical ICU, two mixed medical-surgical ICUs, coronary care unit, or the cardiosurgical ICU) between July 1, 2004, and October 31, 2015. PATIENTS: Adult critically ill patients with hyperammonemia not related to acute or chronic liver failure. We excluded patients with diagnosis of moderate or severe liver disease, hyperbilirubinemia, and patients who denied the use of their medical records. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 3,908 ICU patients with hyperammonemia, 167 (4.5%) had no evidence of acute or chronic liver failure. One-hundred one patients (60.5%) were male with median age of 65.7 years (interquartile range, 50-74.5 yr) and median serum ammonia level of 68 µg/dL (interquartile range, 58-87 µg/dL). Acute encephalopathy was present in 119 patients (71%). Predisposing conditions included malnutrition 27 (16%), gastric bypass six (3.6%), total parenteral nutrition four (2.4%); exposure to valproic acid 17 (10%); status epilepticus 11 (6.6%), high tumour burden 19 (11.3%), and renal failure 82 (49.1%). Urea cycle defects were diagnosed in seven patients (4.1%). Hospital mortality was high (30%), and median ammonia level was higher among the nonsurvivors (74 vs 67 µg/dL; p = 0.05). Deaths were more likely in hyperammonemic patients who were older (p = 0.016), had greater illness severity (higher Acute Physiology and Chronic Health Evaluation III score, p < 0.01), malignancy (p < 0.01), and solid organ transplantation (p = 0.04), whereas seizure disorder was more common in survivors (p = 0.02). After adjustment, serum ammonia level was not associated with increased mortality. CONCLUSIONS: Hyperammonemia occurs in a substantial minority of critically ill patients without liver failure. These patients have a poor prognosis, although ammonia level per se is not independently associated with mortality. Serum ammonia should be measured when risk factors are present, such as nutritional deficiencies and protein refeeding, treatment with valproic acid, high tumour burden, and known or suspected urea cycle abnormalities.

Persistent acute kidney injury following transcatheter aortic valve replacement.

BACKGROUND: Acute kidney injury (AKI) and its severity after transcatheter aortic valve replacement (TAVR) have been associated with worse outcomes. Studies have shown that AKI duration (transient or persistent) affects outcomes independently of AKI severity. This study was undertaken to determine the association, risk factors, and outcomes associated with persistent AKI (pAKI) after TAVR. METHODS: Adult patients undergoing TAVR at Mayo Clinic between January 1, 2008 and June 30, 2014 were enrolled. pAKI was defined as an increased serum creatinine at hospital discharge (≥0.3 mg/dL or ≥50% from baseline). Risk factors associated with pAKI were identified with multivariate logistic regression. RESULTS: A total of 386 patients met the inclusion criteria. Fifty patients (13%) had pAKI. Independent risk factors for pAKI on multivariate analysis included diabetes mellitus (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.29-4.66), prior percutaneous coronary intervention (PCI) (OR, 2.39; 95%CI, 1.24-4.80), intra-aortic balloon pump (IABP) use (OR, 8.14; 95%CI, 1.60-45.78), and blood transfusion (OR, 2.22; 95%CI, 1.15-4.27). Protective factors for pAKI included a higher baseline estimated glomerular filtration rate (eGFR) (OR, 0.83 per 10-mL/min/1.73 m2 increase in eGFR; 95%CI, 0.71-0.99). After adjusting for the Society of Thoracic Surgeons cardiac surgery risk score, pAKI occurrence remained significantly associated with increased 2-year mortality among hospital survivors (hazard ratio, 2.65; 95%CI, 1.51-4.41). CONCLUSION: pAKI was significantly associated with higher mortality risk following TAVR. Baseline eGFR, diabetes mellitus, previous PCI, IABP, and blood transfusion were risk factors for post-procedural pAKI.

High-dose hydroxocobalamin for vasoplegic syndrome causing false blood leak alarm.

Blood leak alarms are important safety features in a hemodialysis machine to protect patients from loss of blood through a rupture in the dialyzer membrane (true alarms). A false blood leak alarm can be triggered by air bubbles or detector malfunction (such as deposits of grease or scale). Hydroxocobalamin is an injectable form of vitamin B12 approved by the US Food and Drug Administration for the treatment of confirmed or suspected cyanide toxicity. Due to observations of an increase in arterial pressure after high-dose hydroxocobalamin infusion for the treatment of acute cyanide poisoning, it has recently been reported as an off-label rescue treatment for post-cardiopulmonary bypass vasoplegic syndrome. We report an 83-year-old man who received hydroxocobalamin following cardiac surgery for treatment of vasoplegic syndrome. The patient developed severe acute kidney injury with volume overload. Hydroxocobalamin interference with the blood leak detector compromised his dialysis treatment. We describe the use of continuous renal replacement therapy to overcome the hydroxocobalamin-related interference with hemodialysis. As the utility of hydroxocobalamin potentially expands, physicians must be aware of its inadvertent effect on renal replacement therapy.