Edward Siew - Academia.edu (original) (raw)

Papers by Edward Siew

Research paper thumbnail of CRP Polymorphisms and Progression of Chronic Kidney Disease in African Americans

Clinical Journal of the American Society of Nephrology, 2010

Chronic inflammation may play a role in chronic kidney disease (CKD) progression. CRP gene polymo... more Chronic inflammation may play a role in chronic kidney disease (CKD) progression. CRP gene polymorphisms are associated with serum C-reactive protein (CRP) concentrations. It is unknown if CRP polymorphisms are associated with CKD progression or modify the effectiveness of anti-hypertensive therapy in delaying CKD progression. We genotyped 642 participants with CKD from the African American Study of Kidney Disease and Hypertension (AASK), selecting five tag polymorphisms: rs2808630, rs1205, rs3093066, rs1417938, and rs3093058. We compared the minor allele frequencies (MAF) of single nucleotide polymorphisms (SNPs) in AASK to MAFs of African Americans from NHANES III. Among AASK participants, we evaluated the association of SNPs with CRP levels and prospectively with a composite: halving the GFR, ESRD, or death. The MAF was higher for the rs2808630_G allele (P = 0.03) and lower for the rs1205_A allele (P = 0.03) in the AASK compared with NHANES III. Among AASK participants, the rs3093058_T allele predicted higher CRP concentrations (P < 0.0001) but not CKD progression. The rs2808630_GG genotype was associated with higher risk of the composite endpoint compared with the AA genotype (P = 0.002). Participants with the rs2808630_GG genotype on angiotensin converting enzyme inhibitors (ACEIs) versus beta blockers had increased risk of progression (P = 0.03). CRP SNPs that were associated with higher levels of CRP did not predict CKD progression. The rs2808630_GG genotype was associated with higher risk of CKD progression, and in patients with this genotype, ACEIs did not slow progression.

Research paper thumbnail of Cigarette Smoke Exposure and the Acute Respiratory Distress Syndrome

Critical care medicine, Jan 22, 2015

The association between cigarette smoke exposure and the acute respiratory distress syndrome in p... more The association between cigarette smoke exposure and the acute respiratory distress syndrome in patients with the most common acute respiratory distress syndrome risk factors of sepsis, pneumonia, and aspiration has not been well studied. The goal of this study was to test the association between biomarker-confirmed cigarette smoking and acute respiratory distress syndrome in a diverse cohort. Prospective cohort. Tertiary care center. Four hundred twenty-six critically ill patients with acute respiratory distress syndrome risk factors (excluding trauma and transfusion) INTERVENTIONS:: None. We obtained smoking histories and measured urine 4-(methylnitrosamino)-1-(3-pyridyl)-1--butanol (a biomarker of cigarette smoke exposure) on urine samples obtained at the time of study enrollment. The association between cigarette smoke exposure and acute respiratory distress syndrome differed based on acute respiratory distress syndrome risk factor (p < 0.02 for interaction). In patients with...

Research paper thumbnail of The growth of acute kidney injury: a rising tide or just closer attention to detail?

Kidney international, 2015

Acute kidney injury (AKI), previously termed acute renal failure, is associated with increased mo... more Acute kidney injury (AKI), previously termed acute renal failure, is associated with increased mortality, prolonged hospital stay, and accelerated chronic kidney disease (CKD). Over the past 2 decades, dramatic rises in the incidences of AKI have been reported, particularly within the United States. The question arises as to whether these changes reflect actual increases in disease incidence, or are potentially explained by the introduction of consensus definitions that rely on small standardized changes in serum creatinine, changes in coding and reimbursement, or increasingly available and more liberal use of dialysis. In this review, we explore the secular trends in AKI incidence in North America and Western Europe and its potential contributors.

Research paper thumbnail of Omega-3 fatty acids inhibit the up-regulation of endothelial chemokines in maintenance hemodialysis patients

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2015

Chronic systemic inflammation is common in patients with chronic kidney disease on dialysis (CKD5... more Chronic systemic inflammation is common in patients with chronic kidney disease on dialysis (CKD5D) and has been considered a key mediator of the increased cardiovascular risk in this patient population. In this study, we tested the hypothesis that supplementation of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) will attenuate the systemic inflammatory process in CKD5D patients. The design was a randomized, double-blinded, placebo controlled pilot trial (NCT00655525). Thirty-eight patients were randomly assigned in a 1 : 1 fashion to receive 2.9 g of eicosapentaenoic acid (C20:5, n-3) plus docosahexaenoic acid (C22:6, n-3) versus placebo for 12 weeks. The primary outcome was change in pro-inflammatory chemokines measured by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). Secondary outcomes were changes in systemic inflammatory markers. Analysis of covariance was used to compare percent change from baseline to 12 weeks. Thirty-one patients completed ...

Research paper thumbnail of Urinary L-FABP predicts poor outcomes in critically ill patients with early acute kidney injury

Kidney International, 2014

Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselect... more Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.

Research paper thumbnail of Real-time pharmacy surveillance and clinical decision support to reduce adverse drug events in acute kidney injury: a randomized, controlled trial

Objectives-Clinical decision support (CDS), such as computerized alerts, improves prescribing in ... more Objectives-Clinical decision support (CDS), such as computerized alerts, improves prescribing in the setting of acute kidney injury (AKI), but considerable opportunity remains to improve patient safety. The authors sought to determine whether pharmacy surveillance of AKI patients could detect and prevent medication errors that are not corrected by automated interventions.

Research paper thumbnail of Laboratory Test Surveillance following Acute Kidney Injury

PLoS ONE, 2014

Background: Patients with hospitalized acute kidney injury (AKI) are at increased risk for accele... more Background: Patients with hospitalized acute kidney injury (AKI) are at increased risk for accelerated loss of kidney function, morbidity, and mortality. We sought to inform efforts at improving post-AKI outcomes by describing the receipt of renalspecific laboratory test surveillance among a large high-risk cohort.

Research paper thumbnail of Diagnosis of Acute Kidney Injury Using Functional and Injury Biomarkers: Workgroup Statements from the Tenth Acute Dialysis Quality Initiative Consensus Conference

Contributions to Nephrology, 2013

Acute kidney injury (AKI) commonly occurs in hospitalized patients and is independently and stron... more Acute kidney injury (AKI) commonly occurs in hospitalized patients and is independently and strongly associates with morbidity and mortality. The clinical benefits of a timely and definitive diagnosis of AKI have not been fully realized due to limitations imposed by the use of serum creatinine and urine output to fulfill diagnostic criteria. These restrictions often lead to diagnostic delays, potential misclassification of actual injury status, and provide little information regarding underlying cause. Novel biomarkers of damage have shown ability to reflect ongoing kidney injury and help further refine existing Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN) diagnostic criteria. A comprehensive review of the published literature to date was performed using previously published methodology of the Acute Dialysis Quality Initiative (ADQI) working group to establish consensus statements regarding (i) the overall implementation of injury biomarkers in the concept of AKI diagnosis, (ii) their clinical use, and (iii) future research. On the basis of published data on the ability of novel damage biomarkers to provide diagnostic and prognostic information on AKI, we recommend that novel damage biomarkers may, in the appropriate clinical setting and context (situation consistent with AKI), be used to diagnose AKI even in the absence of changes in serum creatinine or the presence of oliguria as described in the existing RIFLE/AKIN criteria for diagnosis of AKI. Adding injury biomarkers as a criterion for AKI will complement the ability of RIFLE/AKIN to define AKI. Promising diagnostic injury markers include neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18) and liver-type fatty acid binding protein (L-FABP). However, there are currently insufficient data on damage biomarkers to support their use for AKI staging. Rigorous validation studies measuring the association between the novel damage biomarker(s) and clinically relevant outcomes are needed.

Research paper thumbnail of Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury

Kidney International, 2010

Studies of acute kidney injury (AKI) commonly lack data on pre-admission renal function, often su... more Studies of acute kidney injury (AKI) commonly lack data on pre-admission renal function, often substituting an inpatient or imputed serum creatinine (SCr) as an estimate for "baseline" renal function. We examined the error introduced when applying methods to estimate "baseline" on AKI classification and mortality. Within a cohort of 4863 adults with a known outpatient baseline admitted to Vanderbilt University Hospital between 10/07 and 10/08, the following surrogates were studied:

Research paper thumbnail of Insulin resistance is associated with skeletal muscle protein breakdown in non-diabetic chronic hemodialysis patients

Kidney International, 2007

Deranged protein metabolism is known to complicate uremia. Insulin resistance is evident in chron... more Deranged protein metabolism is known to complicate uremia. Insulin resistance is evident in chronic hemodialysis (CHD) patients. We hypothesized that the degree of insulin resistance would predict protein catabolism in non-diabetic CHD patients. We examined the relationship between Homeostasis Model Assessment (HOMA) and fasting whole-body and skeletal muscle protein turnover in 18 non-diabetic CHD patients using primed-constant infusions of L-(1-13 C) leucine and L-(ring-2 H 5 ) phenylalanine. Mean7s.d. fasting glucose and body mass index were 80.679.8 mg/dl and 25.474.4 kg/m 2 , respectively. Median (interquartile range) HOMA was 1.6 (1.4, 3.9). Mean7s.e.m. skeletal muscle protein synthesis, breakdown, and net balance were 89.57711.67, 97.02713.3, and À7.4477.14 lg/100 ml/min, respectively. Using linear regression, a positive correlation was observed between HOMA and skeletal muscle protein synthesis (R 2 ¼ 0.28; P ¼ 0.024), and breakdown (R 2 ¼ 0.49; P ¼ 0.001). An inverse association between net skeletal muscle protein balance and HOMA was also noted (R 2 ¼ 0.20; P ¼ 0.066). After adjustment for C-reactive protein, only the relationship between HOMA and skeletal muscle protein breakdown persisted (R 2 ¼ 0.49; P ¼ 0.006). There were no significant associations between components of whole-body protein turnover and HOMA. This study demonstrates that insulin resistance is evident in non-diabetic dialysis patients, is associated with skeletal muscle protein breakdown, and represents a novel target for intervention in uremic wasting.

Research paper thumbnail of Distinct injury markers for the early detection and prognosis of incident acute kidney injury in critically ill adults with preserved kidney function

Kidney International, 2013

The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is... more The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is hindered by heterogeneity of injury and the potentially confounding effects of prevalent AKI. Here we examined the ability of urine NGAL (NGAL), L-type fatty acid-binding protein (L-FABP), and cystatin C to predict AKI development, death, and dialysis in a nested case-control study of 380 critically ill adults with an eGFR over 60 ml/min per 1.73 m(2). One-hundred thirty AKI cases were identified following biomarker measurement and were compared with 250 controls without AKI. Areas under the receiver-operator characteristic curves (AUC-ROCs) for discriminating incident AKI from non-AKI were 0.58 (95% CI: 0.52-0.64), 0.59 (0.52-0.65), and 0.50 (0.48-0.57) for urine NGAL, L-FABP, and cystatin C, respectively. The combined AUC-ROC for NGAL and L-FABP was 0.59 (56-0.69). Both urine NGAL and L-FABP independently predicted AKI during multivariate regression; however, risk reclassification indices were mixed. Neither urine biomarker was independently associated with death or acute dialysis (NGAL hazard ratio 1.35 (95% CI: 0.93-1.96), L-FABP 1.15 (0.82-1.61)), although both independently predicted the need for acute dialysis alone (NGAL 3.44 (1.73-6.83), L-FABP 2.36 (1.30-4.25)). Thus, urine NGAL and L-FABP independently associated with the development of incident AKI and receipt of dialysis but exhibited poor discrimination for incident AKI using conventional definitions.

Research paper thumbnail of MCP-1 Gene Activation Marks Acute Kidney Injury

Journal of the American Society of Nephrology, 2011

Monocyte chemoattractant protein 1 (MCP-1) mediates acute ischemic and toxic kidney injury, but w... more Monocyte chemoattractant protein 1 (MCP-1) mediates acute ischemic and toxic kidney injury, but whether this can be used as a biomarker of acute kidney injury (AKI) is unknown. We obtained kidney and urine samples from mice with intrarenal (maleate), prerenal (endotoxemia), or postrenal (ureteral obstruction) injury. We also studied the independent effects of uremia without concomitant kidney injury by performing bilateral ureteral transection in mice. Additionally, we obtained urine samples from APACHE II-matched critically ill patients with or without advancing azotemia (n ϭ 10 in each group). We assayed selected samples for MCP-1, MCP-1 mRNA, and for an activating histone mark (H3K4m3) at urinary fragments of the MCP-1 gene and contrasted the results with those obtained for neutrophil gelatinase-associated lipocalin (NGAL), a comparator "AKI biomarker" gene. Maleate increased urinary MCP-1 protein and mRNA more than the corresponding increases in NGAL. Endotoxemia and ureteral obstruction also increased NGAL and MCP-1 gene expression. Uremia, in the absence of renal injury, induced the NGAL gene, but not MCP-1, suggesting the possibility of better specificity of MCP-1 for AKI. Clinical assessments supported the utility of MCP-1 as a biomarker (e.g., nonoverlapping concentrations of urinary MCP-1 in patients with and without AKI). Elevated levels of urinary MCP-1 mRNA and levels of H3K4m3 at the MCP-1 gene supported MCP-1 gene activation in patients with renal injury. In conclusion, these data suggest that MCP-1 has potential as a biomarker of AKI and provide "proof of concept" that urinary histone assessments provide mechanistic insight among patients with kidney disease.

Research paper thumbnail of Biological Markers of Acute Kidney Injury

Journal of the American Society of Nephrology, 2011

An abrupt change in serum creatinine, the most common indicator of acute kidney injury (AKI), is ... more An abrupt change in serum creatinine, the most common indicator of acute kidney injury (AKI), is strongly linked to poor outcomes across multiple clinical settings. Despite endless attempts to distill the magnitude and timing of a changing serum creatinine into a standardized metric, singular focus on this traditional functional marker obligates the characterization of AKI to remain, at best, retrospective and causally noninformative. The resultant inability to meaningfully segregate critical aspects of injury such as type, onset, propagation, and recovery from ongoing decrements in renal function has hindered successful translation of promising therapeutics. Over the past decade, however, the emerging field of clinical proteomics reinvigorates hope of identifying novel plasma and urine biomarkers to characterize cause and course of kidney injury. Efforts to validate these markers for use in clinical studies now show early promise but face important obstacles including interpretive difficulties inherent in using serum creatinine as a sole comparator for diagnostic performance, a need to better evaluate the incremental performance of new markers above established clinical and biochemical predictors, a relative lack of power to sufficiently examine hard clinical end points, and a potential over-reliance on use alone of receiver operating curves for assessing biomarker utility. Here, we discuss efforts to address these barriers and further ascertain the clinical value of new markers.

Research paper thumbnail of The Inexorable Rise of AKI: Can We Bend the Growth Curve?

Journal of the American Society of Nephrology, 2013

The treatment of anuria should be conservative. If circulatory failure is present, appropriate st... more The treatment of anuria should be conservative. If circulatory failure is present, appropriate steps should be taken to correct it.

Research paper thumbnail of Outpatient Nephrology Referral Rates after Acute Kidney Injury

Journal of the American Society of Nephrology, 2012

AKI associates with an increased risk for the development and progression of CKD and mortality. P... more AKI associates with an increased risk for the development and progression of CKD and mortality. Processes of care after an episode of AKI are not well described. Here, we examined the likelihood of nephrology referral among survivors of AKI at risk for subsequent decline in kidney function in a US Department of Veterans Affairs database. We identified 3929 survivors of AKI hospitalized between January 2003 and December 2008 who had an estimated GFR (eGFR) ,60 ml/min per 1.73 m 2 30 days after peak injury. We analyzed time to referral considering improvement in kidney function (eGFR $60 ml/min per 1.73 m 2 ), dialysis initiation, and death as competing risks over a 12-month surveillance period. Median age was 73 years (interquartile range, 62-79 years) and the prevalence of preadmission kidney dysfunction (baseline eGFR ,60 ml/min per 1.73 m 2 ) was 60%. Overall mortality during the surveillance period was 22%. The cumulative incidence of nephrology referral before dying, initiating dialysis, or experiencing an improvement in kidney function was 8.5% (95% confidence interval, 7.6-9.4). Severity of AKI did not affect referral rates. These data demonstrate that a minority of at-risk survivors are referred for nephrology care after an episode of AKI. Determining how to best identify survivors of AKI who are at highest risk for complications and progression of CKD could facilitate early nephrology-based interventions.

Research paper thumbnail of The Outcome of Neutrophil Gelatinase-Associated Lipocalin-Positive Subclinical Acute Kidney Injury

Journal of the American College of Cardiology, 2011

Research paper thumbnail of A Pilot Study of Active Vitamin D Administration and Insulin Resistance in African American Patients Undergoing Chronic Hemodialysis

Journal of Renal Nutrition, 2013

Insulin resistance (IR) is associated with increased cardiovascular risk in multiple patient popu... more Insulin resistance (IR) is associated with increased cardiovascular risk in multiple patient populations, including those undergoing chronic hemodialysis (CHD). Active vitamin D deficiency has been proposed to play a role in the extent of IR observed in patients with CHD. We postulated that administration of paracalcitol, an active vitamin D medication, influences IR in patients with CHD. This was a pilot randomized controlled trial. Ten prevalent CHD patients receiving a stable dose of paracalcitol were recruited. Paracalcitol was withheld for 8 weeks in all patients (phase I). Parathyroid hormone levels were managed with the calcium-sensing receptor agonist cinacalcet. At week 8, patients were randomized to continue cinacalcet or to restart paracalcitol for 8 weeks (phase II). The primary outcome was the change in IR measured by the glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp (HEGC) method. Secondary outcomes included changes in IR between groups in indirect indices of IR, biomarkers of inflammation, and adipokine levels. The mean age was 49 years (range, 46-57 years) and 40% of patients were women. There was no detectable change in the GDR at the end of phase I (P = .7) when compared with baseline values. There was also no statistically significant difference in GDR between groups at the end of phase II (P = .9). No changes were observed in indirect indices of IR, adipokine levels, or biomarkers of inflammation in either phase. The results of this pilot study suggest that withdrawal of paracalcitol over 8 to 16 weeks and replacement for 8 weeks after withdrawal does not influence IR measured by HEGC in patients receiving CHD.

Research paper thumbnail of Ameliorative Effect of MK-801 on Retinal Ischemia

Journal of Ocular Pharmacology and Therapeutics, 1997

The efficacy of MK-801, an N-methyl-D-aspartate receptor antagonist, was evaluated in a rat model... more The efficacy of MK-801, an N-methyl-D-aspartate receptor antagonist, was evaluated in a rat model of retinal ischemia induced by elevated intraocular pressure. Intraperitoneal injection of MK-801 at 0, 1, 3 and 10 mg/kg was given immediately after reperfusion. At 7 days after reperfusion, the inner retinal thickness, as measured from histologic sections of the retinas, of the 10 mg/kg treated group showed significant beneficial effect, while the other doses had no significant effect. Retinal ganglion cell counts on flat preparations of the retinas showed a beneficial dose dependent effect of MK-801 with the lowest dose showing no effect, 3 mg/kg showing marginal effects and 10 mg/kg showing significant effects. Intravitreal infusion of MK-801 during the ischemic period suppressed ischemia/reperfusion-induced internucleosomal DNA fragmentation measured at 18 hours after the insult as well as retinal tissue responses measured at 7 days. These findings suggested that the NMDA receptors may have an important role in ischemia-reperfusion insult as well as in mediating ischemia-induced apoptosis of retinal neurons. In addition, we demonstrated that pharmacological modulation of apoptotic cell death may affect the final tissue responses in vivo.

Research paper thumbnail of Intravitreal Delivery of Ganciclovir in Rabbits by Transscleral Iontophoresis

Journal of Ocular Pharmacology and Therapeutics, 1994

To avoid the side effects of systemic administration of ganciclovir (GCV) for the treatment of cy... more To avoid the side effects of systemic administration of ganciclovir (GCV) for the treatment of cytomegalovirus (CMV) retinitis, we studied transscleral iontophoresis of GCV into rabbit eyes. After a single application with 20% (w/w) aqueous solution of GCV at 1.0 mA for 15 min gave a vitreal/retinal level of GCV at 74 +/- 17 micrograms/ml at 2 hours as determined by HPLC. At 24 hours after iontophoresis the vitreal/retinal level was above therapeutic level at 4.2 +/- 0.6 micrograms/ml. At 72 hours, there was still detectable level in the vitreous/retina. Hence, transscleral iontophoresis is able to deliver effective dose of GCV into the vitreous. Multiple applications of iontophoresis should be examined as a possible means of CMV treatment.

Research paper thumbnail of The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods

BMC nephrology, 2010

The incidence of acute kidney injury (AKI) has been increasing over time and is associated with a... more The incidence of acute kidney injury (AKI) has been increasing over time and is associated with a high risk of short-term death. Previous studies on hospital-acquired AKI have important methodological limitations, especially their retrospective study designs and limited ability to control for potential confounding factors.

Research paper thumbnail of CRP Polymorphisms and Progression of Chronic Kidney Disease in African Americans

Clinical Journal of the American Society of Nephrology, 2010

Chronic inflammation may play a role in chronic kidney disease (CKD) progression. CRP gene polymo... more Chronic inflammation may play a role in chronic kidney disease (CKD) progression. CRP gene polymorphisms are associated with serum C-reactive protein (CRP) concentrations. It is unknown if CRP polymorphisms are associated with CKD progression or modify the effectiveness of anti-hypertensive therapy in delaying CKD progression. We genotyped 642 participants with CKD from the African American Study of Kidney Disease and Hypertension (AASK), selecting five tag polymorphisms: rs2808630, rs1205, rs3093066, rs1417938, and rs3093058. We compared the minor allele frequencies (MAF) of single nucleotide polymorphisms (SNPs) in AASK to MAFs of African Americans from NHANES III. Among AASK participants, we evaluated the association of SNPs with CRP levels and prospectively with a composite: halving the GFR, ESRD, or death. The MAF was higher for the rs2808630_G allele (P = 0.03) and lower for the rs1205_A allele (P = 0.03) in the AASK compared with NHANES III. Among AASK participants, the rs3093058_T allele predicted higher CRP concentrations (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) but not CKD progression. The rs2808630_GG genotype was associated with higher risk of the composite endpoint compared with the AA genotype (P = 0.002). Participants with the rs2808630_GG genotype on angiotensin converting enzyme inhibitors (ACEIs) versus beta blockers had increased risk of progression (P = 0.03). CRP SNPs that were associated with higher levels of CRP did not predict CKD progression. The rs2808630_GG genotype was associated with higher risk of CKD progression, and in patients with this genotype, ACEIs did not slow progression.

Research paper thumbnail of Cigarette Smoke Exposure and the Acute Respiratory Distress Syndrome

Critical care medicine, Jan 22, 2015

The association between cigarette smoke exposure and the acute respiratory distress syndrome in p... more The association between cigarette smoke exposure and the acute respiratory distress syndrome in patients with the most common acute respiratory distress syndrome risk factors of sepsis, pneumonia, and aspiration has not been well studied. The goal of this study was to test the association between biomarker-confirmed cigarette smoking and acute respiratory distress syndrome in a diverse cohort. Prospective cohort. Tertiary care center. Four hundred twenty-six critically ill patients with acute respiratory distress syndrome risk factors (excluding trauma and transfusion) INTERVENTIONS:: None. We obtained smoking histories and measured urine 4-(methylnitrosamino)-1-(3-pyridyl)-1--butanol (a biomarker of cigarette smoke exposure) on urine samples obtained at the time of study enrollment. The association between cigarette smoke exposure and acute respiratory distress syndrome differed based on acute respiratory distress syndrome risk factor (p < 0.02 for interaction). In patients with...

Research paper thumbnail of The growth of acute kidney injury: a rising tide or just closer attention to detail?

Kidney international, 2015

Acute kidney injury (AKI), previously termed acute renal failure, is associated with increased mo... more Acute kidney injury (AKI), previously termed acute renal failure, is associated with increased mortality, prolonged hospital stay, and accelerated chronic kidney disease (CKD). Over the past 2 decades, dramatic rises in the incidences of AKI have been reported, particularly within the United States. The question arises as to whether these changes reflect actual increases in disease incidence, or are potentially explained by the introduction of consensus definitions that rely on small standardized changes in serum creatinine, changes in coding and reimbursement, or increasingly available and more liberal use of dialysis. In this review, we explore the secular trends in AKI incidence in North America and Western Europe and its potential contributors.

Research paper thumbnail of Omega-3 fatty acids inhibit the up-regulation of endothelial chemokines in maintenance hemodialysis patients

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2015

Chronic systemic inflammation is common in patients with chronic kidney disease on dialysis (CKD5... more Chronic systemic inflammation is common in patients with chronic kidney disease on dialysis (CKD5D) and has been considered a key mediator of the increased cardiovascular risk in this patient population. In this study, we tested the hypothesis that supplementation of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) will attenuate the systemic inflammatory process in CKD5D patients. The design was a randomized, double-blinded, placebo controlled pilot trial (NCT00655525). Thirty-eight patients were randomly assigned in a 1 : 1 fashion to receive 2.9 g of eicosapentaenoic acid (C20:5, n-3) plus docosahexaenoic acid (C22:6, n-3) versus placebo for 12 weeks. The primary outcome was change in pro-inflammatory chemokines measured by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). Secondary outcomes were changes in systemic inflammatory markers. Analysis of covariance was used to compare percent change from baseline to 12 weeks. Thirty-one patients completed ...

Research paper thumbnail of Urinary L-FABP predicts poor outcomes in critically ill patients with early acute kidney injury

Kidney International, 2014

Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselect... more Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.

Research paper thumbnail of Real-time pharmacy surveillance and clinical decision support to reduce adverse drug events in acute kidney injury: a randomized, controlled trial

Objectives-Clinical decision support (CDS), such as computerized alerts, improves prescribing in ... more Objectives-Clinical decision support (CDS), such as computerized alerts, improves prescribing in the setting of acute kidney injury (AKI), but considerable opportunity remains to improve patient safety. The authors sought to determine whether pharmacy surveillance of AKI patients could detect and prevent medication errors that are not corrected by automated interventions.

Research paper thumbnail of Laboratory Test Surveillance following Acute Kidney Injury

PLoS ONE, 2014

Background: Patients with hospitalized acute kidney injury (AKI) are at increased risk for accele... more Background: Patients with hospitalized acute kidney injury (AKI) are at increased risk for accelerated loss of kidney function, morbidity, and mortality. We sought to inform efforts at improving post-AKI outcomes by describing the receipt of renalspecific laboratory test surveillance among a large high-risk cohort.

Research paper thumbnail of Diagnosis of Acute Kidney Injury Using Functional and Injury Biomarkers: Workgroup Statements from the Tenth Acute Dialysis Quality Initiative Consensus Conference

Contributions to Nephrology, 2013

Acute kidney injury (AKI) commonly occurs in hospitalized patients and is independently and stron... more Acute kidney injury (AKI) commonly occurs in hospitalized patients and is independently and strongly associates with morbidity and mortality. The clinical benefits of a timely and definitive diagnosis of AKI have not been fully realized due to limitations imposed by the use of serum creatinine and urine output to fulfill diagnostic criteria. These restrictions often lead to diagnostic delays, potential misclassification of actual injury status, and provide little information regarding underlying cause. Novel biomarkers of damage have shown ability to reflect ongoing kidney injury and help further refine existing Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN) diagnostic criteria. A comprehensive review of the published literature to date was performed using previously published methodology of the Acute Dialysis Quality Initiative (ADQI) working group to establish consensus statements regarding (i) the overall implementation of injury biomarkers in the concept of AKI diagnosis, (ii) their clinical use, and (iii) future research. On the basis of published data on the ability of novel damage biomarkers to provide diagnostic and prognostic information on AKI, we recommend that novel damage biomarkers may, in the appropriate clinical setting and context (situation consistent with AKI), be used to diagnose AKI even in the absence of changes in serum creatinine or the presence of oliguria as described in the existing RIFLE/AKIN criteria for diagnosis of AKI. Adding injury biomarkers as a criterion for AKI will complement the ability of RIFLE/AKIN to define AKI. Promising diagnostic injury markers include neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18) and liver-type fatty acid binding protein (L-FABP). However, there are currently insufficient data on damage biomarkers to support their use for AKI staging. Rigorous validation studies measuring the association between the novel damage biomarker(s) and clinically relevant outcomes are needed.

Research paper thumbnail of Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury

Kidney International, 2010

Studies of acute kidney injury (AKI) commonly lack data on pre-admission renal function, often su... more Studies of acute kidney injury (AKI) commonly lack data on pre-admission renal function, often substituting an inpatient or imputed serum creatinine (SCr) as an estimate for "baseline" renal function. We examined the error introduced when applying methods to estimate "baseline" on AKI classification and mortality. Within a cohort of 4863 adults with a known outpatient baseline admitted to Vanderbilt University Hospital between 10/07 and 10/08, the following surrogates were studied:

Research paper thumbnail of Insulin resistance is associated with skeletal muscle protein breakdown in non-diabetic chronic hemodialysis patients

Kidney International, 2007

Deranged protein metabolism is known to complicate uremia. Insulin resistance is evident in chron... more Deranged protein metabolism is known to complicate uremia. Insulin resistance is evident in chronic hemodialysis (CHD) patients. We hypothesized that the degree of insulin resistance would predict protein catabolism in non-diabetic CHD patients. We examined the relationship between Homeostasis Model Assessment (HOMA) and fasting whole-body and skeletal muscle protein turnover in 18 non-diabetic CHD patients using primed-constant infusions of L-(1-13 C) leucine and L-(ring-2 H 5 ) phenylalanine. Mean7s.d. fasting glucose and body mass index were 80.679.8 mg/dl and 25.474.4 kg/m 2 , respectively. Median (interquartile range) HOMA was 1.6 (1.4, 3.9). Mean7s.e.m. skeletal muscle protein synthesis, breakdown, and net balance were 89.57711.67, 97.02713.3, and À7.4477.14 lg/100 ml/min, respectively. Using linear regression, a positive correlation was observed between HOMA and skeletal muscle protein synthesis (R 2 ¼ 0.28; P ¼ 0.024), and breakdown (R 2 ¼ 0.49; P ¼ 0.001). An inverse association between net skeletal muscle protein balance and HOMA was also noted (R 2 ¼ 0.20; P ¼ 0.066). After adjustment for C-reactive protein, only the relationship between HOMA and skeletal muscle protein breakdown persisted (R 2 ¼ 0.49; P ¼ 0.006). There were no significant associations between components of whole-body protein turnover and HOMA. This study demonstrates that insulin resistance is evident in non-diabetic dialysis patients, is associated with skeletal muscle protein breakdown, and represents a novel target for intervention in uremic wasting.

Research paper thumbnail of Distinct injury markers for the early detection and prognosis of incident acute kidney injury in critically ill adults with preserved kidney function

Kidney International, 2013

The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is... more The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is hindered by heterogeneity of injury and the potentially confounding effects of prevalent AKI. Here we examined the ability of urine NGAL (NGAL), L-type fatty acid-binding protein (L-FABP), and cystatin C to predict AKI development, death, and dialysis in a nested case-control study of 380 critically ill adults with an eGFR over 60 ml/min per 1.73 m(2). One-hundred thirty AKI cases were identified following biomarker measurement and were compared with 250 controls without AKI. Areas under the receiver-operator characteristic curves (AUC-ROCs) for discriminating incident AKI from non-AKI were 0.58 (95% CI: 0.52-0.64), 0.59 (0.52-0.65), and 0.50 (0.48-0.57) for urine NGAL, L-FABP, and cystatin C, respectively. The combined AUC-ROC for NGAL and L-FABP was 0.59 (56-0.69). Both urine NGAL and L-FABP independently predicted AKI during multivariate regression; however, risk reclassification indices were mixed. Neither urine biomarker was independently associated with death or acute dialysis (NGAL hazard ratio 1.35 (95% CI: 0.93-1.96), L-FABP 1.15 (0.82-1.61)), although both independently predicted the need for acute dialysis alone (NGAL 3.44 (1.73-6.83), L-FABP 2.36 (1.30-4.25)). Thus, urine NGAL and L-FABP independently associated with the development of incident AKI and receipt of dialysis but exhibited poor discrimination for incident AKI using conventional definitions.

Research paper thumbnail of MCP-1 Gene Activation Marks Acute Kidney Injury

Journal of the American Society of Nephrology, 2011

Monocyte chemoattractant protein 1 (MCP-1) mediates acute ischemic and toxic kidney injury, but w... more Monocyte chemoattractant protein 1 (MCP-1) mediates acute ischemic and toxic kidney injury, but whether this can be used as a biomarker of acute kidney injury (AKI) is unknown. We obtained kidney and urine samples from mice with intrarenal (maleate), prerenal (endotoxemia), or postrenal (ureteral obstruction) injury. We also studied the independent effects of uremia without concomitant kidney injury by performing bilateral ureteral transection in mice. Additionally, we obtained urine samples from APACHE II-matched critically ill patients with or without advancing azotemia (n ϭ 10 in each group). We assayed selected samples for MCP-1, MCP-1 mRNA, and for an activating histone mark (H3K4m3) at urinary fragments of the MCP-1 gene and contrasted the results with those obtained for neutrophil gelatinase-associated lipocalin (NGAL), a comparator "AKI biomarker" gene. Maleate increased urinary MCP-1 protein and mRNA more than the corresponding increases in NGAL. Endotoxemia and ureteral obstruction also increased NGAL and MCP-1 gene expression. Uremia, in the absence of renal injury, induced the NGAL gene, but not MCP-1, suggesting the possibility of better specificity of MCP-1 for AKI. Clinical assessments supported the utility of MCP-1 as a biomarker (e.g., nonoverlapping concentrations of urinary MCP-1 in patients with and without AKI). Elevated levels of urinary MCP-1 mRNA and levels of H3K4m3 at the MCP-1 gene supported MCP-1 gene activation in patients with renal injury. In conclusion, these data suggest that MCP-1 has potential as a biomarker of AKI and provide "proof of concept" that urinary histone assessments provide mechanistic insight among patients with kidney disease.

Research paper thumbnail of Biological Markers of Acute Kidney Injury

Journal of the American Society of Nephrology, 2011

An abrupt change in serum creatinine, the most common indicator of acute kidney injury (AKI), is ... more An abrupt change in serum creatinine, the most common indicator of acute kidney injury (AKI), is strongly linked to poor outcomes across multiple clinical settings. Despite endless attempts to distill the magnitude and timing of a changing serum creatinine into a standardized metric, singular focus on this traditional functional marker obligates the characterization of AKI to remain, at best, retrospective and causally noninformative. The resultant inability to meaningfully segregate critical aspects of injury such as type, onset, propagation, and recovery from ongoing decrements in renal function has hindered successful translation of promising therapeutics. Over the past decade, however, the emerging field of clinical proteomics reinvigorates hope of identifying novel plasma and urine biomarkers to characterize cause and course of kidney injury. Efforts to validate these markers for use in clinical studies now show early promise but face important obstacles including interpretive difficulties inherent in using serum creatinine as a sole comparator for diagnostic performance, a need to better evaluate the incremental performance of new markers above established clinical and biochemical predictors, a relative lack of power to sufficiently examine hard clinical end points, and a potential over-reliance on use alone of receiver operating curves for assessing biomarker utility. Here, we discuss efforts to address these barriers and further ascertain the clinical value of new markers.

Research paper thumbnail of The Inexorable Rise of AKI: Can We Bend the Growth Curve?

Journal of the American Society of Nephrology, 2013

The treatment of anuria should be conservative. If circulatory failure is present, appropriate st... more The treatment of anuria should be conservative. If circulatory failure is present, appropriate steps should be taken to correct it.

Research paper thumbnail of Outpatient Nephrology Referral Rates after Acute Kidney Injury

Journal of the American Society of Nephrology, 2012

AKI associates with an increased risk for the development and progression of CKD and mortality. P... more AKI associates with an increased risk for the development and progression of CKD and mortality. Processes of care after an episode of AKI are not well described. Here, we examined the likelihood of nephrology referral among survivors of AKI at risk for subsequent decline in kidney function in a US Department of Veterans Affairs database. We identified 3929 survivors of AKI hospitalized between January 2003 and December 2008 who had an estimated GFR (eGFR) ,60 ml/min per 1.73 m 2 30 days after peak injury. We analyzed time to referral considering improvement in kidney function (eGFR $60 ml/min per 1.73 m 2 ), dialysis initiation, and death as competing risks over a 12-month surveillance period. Median age was 73 years (interquartile range, 62-79 years) and the prevalence of preadmission kidney dysfunction (baseline eGFR ,60 ml/min per 1.73 m 2 ) was 60%. Overall mortality during the surveillance period was 22%. The cumulative incidence of nephrology referral before dying, initiating dialysis, or experiencing an improvement in kidney function was 8.5% (95% confidence interval, 7.6-9.4). Severity of AKI did not affect referral rates. These data demonstrate that a minority of at-risk survivors are referred for nephrology care after an episode of AKI. Determining how to best identify survivors of AKI who are at highest risk for complications and progression of CKD could facilitate early nephrology-based interventions.

Research paper thumbnail of The Outcome of Neutrophil Gelatinase-Associated Lipocalin-Positive Subclinical Acute Kidney Injury

Journal of the American College of Cardiology, 2011

Research paper thumbnail of A Pilot Study of Active Vitamin D Administration and Insulin Resistance in African American Patients Undergoing Chronic Hemodialysis

Journal of Renal Nutrition, 2013

Insulin resistance (IR) is associated with increased cardiovascular risk in multiple patient popu... more Insulin resistance (IR) is associated with increased cardiovascular risk in multiple patient populations, including those undergoing chronic hemodialysis (CHD). Active vitamin D deficiency has been proposed to play a role in the extent of IR observed in patients with CHD. We postulated that administration of paracalcitol, an active vitamin D medication, influences IR in patients with CHD. This was a pilot randomized controlled trial. Ten prevalent CHD patients receiving a stable dose of paracalcitol were recruited. Paracalcitol was withheld for 8 weeks in all patients (phase I). Parathyroid hormone levels were managed with the calcium-sensing receptor agonist cinacalcet. At week 8, patients were randomized to continue cinacalcet or to restart paracalcitol for 8 weeks (phase II). The primary outcome was the change in IR measured by the glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp (HEGC) method. Secondary outcomes included changes in IR between groups in indirect indices of IR, biomarkers of inflammation, and adipokine levels. The mean age was 49 years (range, 46-57 years) and 40% of patients were women. There was no detectable change in the GDR at the end of phase I (P = .7) when compared with baseline values. There was also no statistically significant difference in GDR between groups at the end of phase II (P = .9). No changes were observed in indirect indices of IR, adipokine levels, or biomarkers of inflammation in either phase. The results of this pilot study suggest that withdrawal of paracalcitol over 8 to 16 weeks and replacement for 8 weeks after withdrawal does not influence IR measured by HEGC in patients receiving CHD.

Research paper thumbnail of Ameliorative Effect of MK-801 on Retinal Ischemia

Journal of Ocular Pharmacology and Therapeutics, 1997

The efficacy of MK-801, an N-methyl-D-aspartate receptor antagonist, was evaluated in a rat model... more The efficacy of MK-801, an N-methyl-D-aspartate receptor antagonist, was evaluated in a rat model of retinal ischemia induced by elevated intraocular pressure. Intraperitoneal injection of MK-801 at 0, 1, 3 and 10 mg/kg was given immediately after reperfusion. At 7 days after reperfusion, the inner retinal thickness, as measured from histologic sections of the retinas, of the 10 mg/kg treated group showed significant beneficial effect, while the other doses had no significant effect. Retinal ganglion cell counts on flat preparations of the retinas showed a beneficial dose dependent effect of MK-801 with the lowest dose showing no effect, 3 mg/kg showing marginal effects and 10 mg/kg showing significant effects. Intravitreal infusion of MK-801 during the ischemic period suppressed ischemia/reperfusion-induced internucleosomal DNA fragmentation measured at 18 hours after the insult as well as retinal tissue responses measured at 7 days. These findings suggested that the NMDA receptors may have an important role in ischemia-reperfusion insult as well as in mediating ischemia-induced apoptosis of retinal neurons. In addition, we demonstrated that pharmacological modulation of apoptotic cell death may affect the final tissue responses in vivo.

Research paper thumbnail of Intravitreal Delivery of Ganciclovir in Rabbits by Transscleral Iontophoresis

Journal of Ocular Pharmacology and Therapeutics, 1994

To avoid the side effects of systemic administration of ganciclovir (GCV) for the treatment of cy... more To avoid the side effects of systemic administration of ganciclovir (GCV) for the treatment of cytomegalovirus (CMV) retinitis, we studied transscleral iontophoresis of GCV into rabbit eyes. After a single application with 20% (w/w) aqueous solution of GCV at 1.0 mA for 15 min gave a vitreal/retinal level of GCV at 74 +/- 17 micrograms/ml at 2 hours as determined by HPLC. At 24 hours after iontophoresis the vitreal/retinal level was above therapeutic level at 4.2 +/- 0.6 micrograms/ml. At 72 hours, there was still detectable level in the vitreous/retina. Hence, transscleral iontophoresis is able to deliver effective dose of GCV into the vitreous. Multiple applications of iontophoresis should be examined as a possible means of CMV treatment.

Research paper thumbnail of The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods

BMC nephrology, 2010

The incidence of acute kidney injury (AKI) has been increasing over time and is associated with a... more The incidence of acute kidney injury (AKI) has been increasing over time and is associated with a high risk of short-term death. Previous studies on hospital-acquired AKI have important methodological limitations, especially their retrospective study designs and limited ability to control for potential confounding factors.