Michael Heung

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).

Fluid overload at initiation of renal replacement therapy is associated with lack of renal recovery in patients with acute kidney injury

BACKGROUND Patients with acute kidney injury (AKI) requiring initiation of renal replacement therapy (RRT) have poor short- and long-term outcomes, including the development of dialysis dependence. Currently, little is known about what factors may predict renal recovery in this population. METHODS We conducted a single-center, retrospective analysis of 170 hospitalized adult patients with AKI attributed to acute tubular necrosis who required inpatient initiation of RRT. Data collection included patient characteristics, laboratory data, details of hospital course and degree of fluid overload at RRT initiation. The primary outcome was recovery of renal function to dialysis independence. RESULTS Within 1 year of RRT initiation, 35.9% (61/170) of patients reached the primary end point of renal recovery. The median (interquartile range) duration of RRT was 11 (3-33) days and 83.6% (51/61) recovered prior to hospital discharge. Recovering patients had significantly less fluid overload at the time of RRT initiation compared to non-recovering patients (3.5 versus 9.3%, P = 0.004). In multivariate Cox proportional hazard regression analysis, a rise in percent fluid overload at dialysis initiation remained a significant negative predictor of renal recovery (hazard ratio 0.97, 95% confidence interval 0.95-1.00, P = 0.024). CONCLUSIONS In patients with AKI, a higher degree of fluid overload at RRT initiation predicts worse renal recovery at 1 year. Clinical trials are needed to determine whether interventions targeting fluid overload may improve patient and renal outcomes.

Fluid overload and fluid removal in pediatric patients on extracorporeal membrane oxygenation requiring continuous renal replacement therapy.

Objective:In pediatric patients, fluid overload at continuous renal replacement therapy initiation is associated with increased mortality. The aim of this study was to characterize the association between fluid overload at continuous renal replacement therapy initiation, fluid removal during continuous renal replacement therapy, the kinetics of fluid removal and mortality in a large pediatric population receiving continuous renal replacement therapy while on extracorporeal membrane oxygenation. Design:Retrospective chart review. Setting:Tertiary children’s hospital. Patients:Extracorporeal membrane oxygenation patients requiring continuous renal replacement therapy from July 2006 to September 2010. Interventions:None. Measurements and Main Results:Overall intensive care unit survival was 34% for 53 patients that were initiated on continuous renal replacement therapy while on extracorporeal membrane oxygenation during the study period. Median fluid overload at continuous renal replacement therapy initiation was significantly lower in survivors compared to nonsurvivors (24.5% vs. 38%, p = .006). Median fluid overload at continuous renal replacement therapy discontinuation was significantly lower in survivors compared to nonsurvivors (7.1% vs. 17.5%, p = .035). After adjusting for percent fluid overload at continuous renal replacement therapy initiation, age, and severity of illness, the change in fluid overload at continuous renal replacement therapy discontinuation was not significantly associated with mortality (p = .212). Models investigating the rates of fluid removal in different periods, age, severity of illness, and fluid overload at continuous renal replacement therapy initiation found that fluid overload at continuous renal replacement therapy initiation was the most consistent predictor of survival. Conclusions:Our data demonstrate an association between fluid overload at continuous renal replacement therapy initiation and mortality in pediatric patients receiving extracorporeal membrane oxygenation. The degree of fluid overload at continuous renal replacement therapy discontinuation is also associated with mortality, but appears to reflect the effect of fluid overload at initiation. Furthermore, correction of fluid overload to ⩽10% was not associated with improved survival. These results suggest that intervening prior to the development of significant fluid overload may be more clinically effective than attempting fluid removal after significant fluid overload has developed. Our findings suggest a role for earlier initiation of continuous renal replacement therapy in this population, and warrant further clinical studies.

Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis.

Objective:To investigate daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis to develop dosing recommendations. Design:Prospective, open-label pharmacokinetic study. Setting:Intensive care units located within a teaching medical center. Patients:Eight adults with known/suspected Gram-positive infections receiving continuous venovenous hemodialysis and daptomycin. Interventions:Daptomycin at 8 mg/kg intravenously over 30 mins. Serial blood and effluent samples were collected over the next 48 hrs. Daptomycin protein binding was determined by equilibrium dialysis. Daptomycin continuous venovenous hemodialysis transmembrane clearance was determined by dividing daptomycin effluent by serum concentrations and multiplying by mean effluent production rate for each subject. Equations describing a two-compartment, open-pharmacokinetic model were fitted to each subjects daptomycin concentration-time data and pharmacokinetic parameters were determined by standard methods. Serum concentration-time profiles were simulated for two daptomycin regimens (8 mg/kg every 48 hrs and 4 mg/kg every 24 hrs). Measurements and Main results:A total of 7.7 ± 0.6 mg/kg (mean ± sd) of daptomycin was administered, resulting in an observed peak concentration of 81.2 ± 19.0 &mgr;g/mL. Daptomycin steady-state volume of distribution (0.23 ± 0.14 L/kg) and free fraction (17.5% ± 5.0%) were increased in critically ill subjects receiving continuous venovenous hemodialysis compared with previous values reported in healthy volunteers. Daptomycin transmembrane clearance (6.3 ± 2.9 mL/min) accounted for more than half of total clearance (11.3 ± 4.7 mL/min). Simulations demonstrated 8 mg/kg daptomycin every 48 hrs would result in higher peak (88.8 ± 20.0 &mgr;g/mL vs. 53.0 ± 12.3 &mgr;g/mL) and lower trough concentrations (7.2 ± 5.2 &mgr;g/mL vs. 12.3 ± 5.1 &mgr;g/mL) than 4 mg/kg every 24 hrs. Conclusions:Daptomycin at 8 mg/kg every 48 hrs in critically ill patients receiving continuous venovenous hemodialysis resulted in good drug exposure, achieved high peak concentrations to maximize daptomycins concentration-dependent activity, and resulted in trough concentration that would minimize the risk of myopathy. ClinicalTrials.gov Identifier:NCT00663403.

Predicting progression to chronic kidney disease after recovery from acute kidney injury.

Purpose of reviewThis review examines the association between acute kidney injury (AKI) and subsequent risk for chronic kidney disease (CKD) development. The discussion focuses on patients who fully recover from an episode of AKI, the majority of whom do not receive follow-up care with nephrology services. Recent findingsSeveral studies have demonstrated a strong association between AKI and later CKD risk. Animal models provide evidence for a causal link between AKI and CKD while also elucidating some of the potential mechanisms for this progression. Large observational studies have quantified the risk of CKD following AKI recovery, and clinical and emerging biomarker risk factors have been identified. SummaryThe association between AKI with incomplete recovery or nonrecovery and CKD is evident. Recent studies demonstrate that even AKI with apparent full recovery confers an increased risk for subsequent CKD development. Risk prediction models have been developed and require further refinement and validation. The ability to identify patients with AKI recovery who are at high risk for later CKD development is an important clinical and research goal, as there exists a significant opportunity to improve care in this population.

Vulnerable populations and the association between periodontal and chronic kidney disease.

BACKGROUND AND OBJECTIVES Recent studies suggest an overall association between chronic kidney disease (CKD) and periodontal disease, but it is unknown whether this association is similar across various subpopulations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study was a cross-sectional analysis of 2001 to 2004 National Health and Nutrition Examination Survey data. CKD was defined as a urinary albumin-to-creatinine ratio ≥30 mg/g or estimated GFR of 15 to 59 ml/min per 1.73 m(2). Adjusted odds ratios were calculated using multivariable logistic regression with U.S. population-based weighting. RESULTS These analyses included 6199 dentate adult participants (aged 21 to 75 years) with periodontal exams. The estimated prevalences of moderate/severe periodontal disease and CKD were 5.3% and 10.6%, respectively. Periodontal disease was associated with >2-fold higher risk of CKD that was moderately attenuated after adjustment for age, gender, race/ethnicity, tobacco use, hypertension, diabetes, educational attainment, poverty index ratio, and dental care use. There were no statistically significant interactions between periodontal disease and race/ethnicity, educational attainment, or poverty status. Less-than-recommended dental care use was associated with periodontal disease and CKD and was increasingly prevalent among nonwhites, lower educational attainment, and lower poverty status. CONCLUSIONS The association between periodontal disease and CKD is not significantly different among subgroups. However, because nonwhites, those with a lower educational level, and the poor less frequently report use of recommended dental care, the association between periodontal disease and kidney function over time may become stronger among these groups and warrants further investigation.

Intradialytic Administration of Daptomycin in End Stage Renal Disease Patients on Hemodialysis

BACKGROUND AND OBJECTIVES Infusion of intravenous antibiotics after hemodialysis (HD) may delay initiation of treatment for the next HD shift. Intradialytic administration of drugs such as vancomycin during the final hour of HD obviates these delays. Daptomycin has potent activity against Gram-positive bacteria, but the manufacturer recommends that the dose be infused after HD ends. This study determined the pharmacokinetics of intradialytically dosed daptomycin in patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This prospective crossover study compared single-dose daptomycin (6 mg/kg, 30-min intravenous infusion) pharmacokinetics administered after HD versus during the last part of HD with high-permeability (HP) and low-permeability (LP) dialyzers to seven patients who had ESRD and were on thrice-weekly HD. Serial blood samples were collected to determine daptomycin serum concentrations and protein binding. Statistical analysis was done using linear mixed model analysis. RESULTS The maximum serum concentration observed with a 6 mg/kg post-HD dose was 61.1 +/- 7.6 microg/ml with a mean protein binding of 89.2%. Intradialytic daptomycin administration resulted in reduced maximum serum concentration and area under the curve values that were approximately 12 to 20% lower when administered during HD with LP dialyzers and approximately 35% lower with HP dialyzers. CONCLUSIONS Intradialytic daptomycin administration during the last 30 min of HD is feasible, provided that larger dosages are used to compensate for intradialytic drug loss. On the basis of our findings, intradialytic doses of approximately 7 mg/kg (LP) or approximately 9 mg/kg (HP) theoretically should be bioequivalent to 6 mg/kg infused after HD. The calculated dosages are mathematically driven and must be validated in prospective clinical trials.

Promoting Kidney Function Recovery in Patients with AKI Requiring RRT

AKI requiring RRT is associated with high mortality, morbidity, and long-term consequences, including CKD and ESRD. Many patients never recover kidney function; in others, kidney function improves over a period of many weeks or months. Methodologic constraints of the available literature limit our understanding of the recovery process and hamper adequate intervention. Current management strategies have focused on acute care and short-term mortality, but new data indicate that long-term consequences of AKI requiring RRT are substantial. Promotion of kidney function recovery is a neglected focus of research and intervention. This lack of emphasis on recovery is illustrated by the relative paucity of research in this area and by the lack of demonstrated effective management strategies. In this article the epidemiologic implications of kidney recovery after AKI requiring RRT are discussed, the available literature and its methodologic constraints are reviewed, and strategies to improve the understanding of factors that affect kidney function recovery are proposed. Measures to promote kidney function recovery are a serious unmet need, with a great potential to improve short- and long-term patient outcomes.

A Successful Approach to Fall Prevention in an Outpatient Hemodialysis Center

BACKGROUND AND OBJECTIVES Hemodialysis patients are at high risk both for falling and for serious complications associated with falls, but few fall studies have specifically focused on this population. Falls occurring in an outpatient dialysis unit were reviewed to identify contributing factors and implement interventions designed to reduce fall risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A root cause analysis of all fall incidents occurring at an outpatient hemodialysis center during a 4-year period was conducted. A targeted intervention program to reduce falls was then implemented. Risk of falls in the postintervention period was compared with that of the baseline period. RESULTS In the baseline period, a total of 22 falls occurred involving 14 patients and 8 staff members or visitors (incidence of 50 falls per 100,000 dialysis treatments). Root cause analyses identified staff educational deficits and environmental hazards as the most significant risk factors for fall incidents. After an interventional period that focused on formal staff education and environmental modifications, a total of only 3 additional falls (2 patients and 1 staff member) during 21 months of follow-up (14 falls per 100,000 dialysis treatments, P = 0.01) were observed. CONCLUSIONS Several modifiable risk factors for falls occurring in the high-risk setting of an outpatient hemodialysis unit were identified as a result of this formal analysis of fall incidents. Through a targeted series of interventions, a marked reduction in fall risk was achieved.

Exploring Potential Reasons for the Temporal Trend in Dialysis-Requiring AKI in the United States

BACKGROUND AND OBJECTIVES The population incidence of dialysis-requiring AKI has risen substantially in the last decade in the United States, and factors associated with this temporal trend are not well known. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a retrospective cohort study using data from the Nationwide Inpatient Sample, a United States nationally representative database of hospitalizations from 2007 to 2009. We used validated International Classification of Diseases, Ninth Revision codes to identify hospitalizations with dialysis-requiring AKI and then, selected the diagnostic and procedure codes most highly associated with dialysis-requiring AKI in 2009. We applied multivariable logistic regression adjusting for demographics and used a backward selection technique to identify a set of diagnoses or a set of procedures that may be a driver for this changing risk in dialysis-requiring AKI. RESULTS From 2007 to 2009, the population incidence of dialysis-requiring AKI increased by 11% per year (95% confidence interval, 1.07 to 1.16; P<0.001). Using backward selection, we found that the temporal trend in the six diagnoses, septicemia, hypertension, respiratory failure, coagulation/hemorrhagic disorders, shock, and liver disease, sufficiently and fully accounted for the temporal trend in dialysis-requiring AKI. In contrast, temporal trends in 15 procedures most commonly associated with dialysis-requiring AKI did not account for the increasing dialysis-requiring AKI trend. CONCLUSIONS The increasing risk of dialysis-requiring AKI among hospitalized patients in the United States was highly associated with the changing burden of six acute and chronic conditions but not with surgeries and procedures.