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Bridging Translation by Improving Preclinical Study Design in AKI.
de Caestecker M, Humphreys BD, Liu KD, Fissell WH, Cerda J, Nolin TD, Askenazi D, Mour G, Harrell FE, Pullen N, Okusa MD, Faubel S, ASN AKI Advisory Group
(2015) J Am Soc Nephrol 26: 2905-16
MeSH Terms: Acetylcysteine, Acute Kidney Injury, Animals, Contrast Media, Disease Models, Animal, Erythropoietin, Free Radical Scavengers, Humans, Research Design, Sodium Bicarbonate, Translational Medical Research
Show Abstract · Added February 22, 2016
Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.
Copyright © 2015 by the American Society of Nephrology.
0 Communities
2 Members
0 Resources
11 MeSH Terms
Disparities in Electronic Health Record Patient Portal Use in Nephrology Clinics.
Jhamb M, Cavanaugh KL, Bian A, Chen G, Ikizler TA, Unruh ML, Abdel-Kader K
(2015) Clin J Am Soc Nephrol 10: 2013-22
MeSH Terms: Adult, Aged, Aged, 80 and over, Electronic Health Records, Female, Humans, Internet, Male, Middle Aged, Nephrology, Retrospective Studies
Show Abstract · Added November 5, 2015
BACKGROUND AND OBJECTIVES - Electronic health record (EHR) patient portals allow individuals to access their medical information with the intent of patient empowerment. However, little is known about portal use in nephrology patients. We addressed this gap by characterizing adoption of an EHR portal, assessing secular trends, and examining the association of portal adoption and BP control (<140/90 mmHg).
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - Patients seen between January 1, 2010, and December 31, 2012, at any of four university-affiliated nephrology offices who had at least one additional nephrology follow-up visit before June 30, 2013, were included. Sociodemographic characteristics, comorbidities, clinical measurements, and office visits were abstracted from the EHR. Neighborhood median household income was obtained from the American Community Survey 2012.
RESULTS - Of 2803 patients, 1098 (39%) accessed the portal. Over 87% of users reviewed laboratory results, 85% reviewed their medical information (e.g., medical history), 85% reviewed or altered appointments, 77% reviewed medications, 65% requested medication refills, and 31% requested medical advice from their renal provider. In adjusted models, older age, African-American race (odds ratio [OR], 0.50; 95% confidence interval [95% CI], 0.39 to 0.64), Medicaid status (OR, 0.53; 95% CI, 0.36 to 0.77), and lower neighborhood median household income were associated with not accessing the portal. Portal adoption increased over time (2011 versus 2010: OR, 1.38 [95% CI, 1.09 to 1.75]; 2012 versus 2010: OR, 1.95 [95% CI, 1.44 to 2.64]). Portal adoption was correlated with BP control in patients with a diagnosis of hypertension; however, in the fully adjusted model this was somewhat attenuated and no longer statistically significant (OR, 1.11; 95% CI, 0.99 to 1.24).
CONCLUSION - While portal adoption appears to be increasing, greater attention is needed to understand why vulnerable populations do not access it. Future research should examine barriers to the use of e-health technologies in underserved patients with CKD, interventions to address them, and their potential to improve outcomes.
Copyright © 2015 by the American Society of Nephrology.
0 Communities
3 Members
0 Resources
11 MeSH Terms
HDL: Beyond Atheroprotection.
Kon V, Linton MF
(2016) J Am Soc Nephrol 27: 341-4
MeSH Terms: Cholesterol, HDL, Female, Humans, Kidney Transplantation, Male
Added April 10, 2018
0 Communities
1 Members
0 Resources
MeSH Terms
Predictors of Recurrent AKI.
Siew ED, Parr SK, Abdel-Kader K, Eden SK, Peterson JF, Bansal N, Hung AM, Fly J, Speroff T, Ikizler TA, Matheny ME
(2016) J Am Soc Nephrol 27: 1190-200
MeSH Terms: Acute Kidney Injury, Aged, Cohort Studies, Female, Humans, Male, Middle Aged, Recurrence, Retrospective Studies, Risk Assessment, Risk Factors
Show Abstract · Added August 20, 2015
Recurrent AKI is common among patients after hospitalized AKI and is associated with progressive CKD. In this study, we identified clinical risk factors for recurrent AKI present during index AKI hospitalizations that occurred between 2003 and 2010 using a regional Veterans Administration database in the United States. AKI was defined as a 0.3 mg/dl or 50% increase from a baseline creatinine measure. The primary outcome was hospitalization with recurrent AKI within 12 months of discharge from the index hospitalization. Time to recurrent AKI was examined using Cox regression analysis, and sensitivity analyses were performed using a competing risk approach. Among 11,683 qualifying AKI hospitalizations, 2954 patients (25%) were hospitalized with recurrent AKI within 12 months of discharge. Median time to recurrent AKI within 12 months was 64 (interquartile range 19-167) days. In addition to known demographic and comorbid risk factors for AKI, patients with longer AKI duration and those whose discharge diagnosis at index AKI hospitalization included congestive heart failure (primary diagnosis), decompensated advanced liver disease, cancer with or without chemotherapy, acute coronary syndrome, or volume depletion, were at highest risk for being hospitalized with recurrent AKI. Risk factors identified were similar when a competing risk model for death was applied. In conclusion, several inpatient conditions associated with AKI may increase the risk for recurrent AKI. These findings should facilitate risk stratification, guide appropriate patient referral after AKI, and help generate potential risk reduction strategies. Efforts to identify modifiable factors to prevent recurrent AKI in these patients are warranted.
Copyright © 2016 by the American Society of Nephrology.
0 Communities
3 Members
0 Resources
11 MeSH Terms
Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion.
Qi Y, Wang X, Rose KL, MacDonald WH, Zhang B, Schey KL, Luther JM
(2016) J Am Soc Nephrol 27: 646-56
MeSH Terms: Adult, Aldosterone, Cross-Over Studies, Epithelial Sodium Channels, Exosomes, Female, Humans, Male, Renin-Angiotensin System, Sodium, Dietary
Show Abstract · Added November 30, 2015
Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies.
Copyright © 2016 by the American Society of Nephrology.
0 Communities
3 Members
0 Resources
10 MeSH Terms
Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI.
Chiba T, Skrypnyk NI, Skvarca LB, Penchev R, Zhang KX, Rochon ER, Fall JL, Paueksakon P, Yang H, Alford CE, Roman BL, Zhang MZ, Harris R, Hukriede NA, de Caestecker MP
(2016) J Am Soc Nephrol 27: 495-508
MeSH Terms: Acute Kidney Injury, Animals, Macrophages, Male, Mice, Mice, Inbred BALB C, Signal Transduction, Tretinoin
Show Abstract · Added June 29, 2015
Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of AKI, but little is known about the regulation of this pathway and what role it has in regulating injury and repair after AKI. In these studies, we show that RA signaling is activated in mouse and zebrafish models of AKI, and that these responses limit the extent of injury and promote normal repair. These effects were mediated through a novel mechanism by which RA signaling coordinated the dynamic equilibrium of inflammatory M1 spectrum versus alternatively activated M2 spectrum macrophages. Our data suggest that locally synthesized RA represses proinflammatory macrophages, thereby reducing macrophage-dependent injury post-AKI, and activates RA signaling in injured tubular epithelium, which in turn promotes alternatively activated M2 spectrum macrophages. Because RA signaling has an essential role in kidney development but is repressed in the adult, these findings provide evidence of an embryonic signaling pathway that is reactivated after AKI and involved in reducing injury and enhancing repair.
Copyright © 2016 by the American Society of Nephrology.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Furosemide Stress Test and Biomarkers for the Prediction of AKI Severity.
Koyner JL, Davison DL, Brasha-Mitchell E, Chalikonda DM, Arthur JM, Shaw AD, Tumlin JA, Trevino SA, Bennett MR, Kimmel PL, Seneff MG, Chawla LS
(2015) J Am Soc Nephrol 26: 2023-31
MeSH Terms: Acute Kidney Injury, Acute-Phase Proteins, Aged, Albuminuria, Biomarkers, Creatinine, Disease Progression, Diuretics, Female, Furosemide, Hepatitis A Virus Cellular Receptor 1, Humans, Insulin-Like Growth Factor Binding Proteins, Interleukin-18, Lipocalin-2, Lipocalins, Male, Membrane Glycoproteins, Middle Aged, Proto-Oncogene Proteins, Receptors, Virus, Severity of Illness Index, Sodium, Tissue Inhibitor of Metalloproteinase-2, Uromodulin
Show Abstract · Added October 20, 2015
Clinicians have access to limited tools that predict which patients with early AKI will progress to more severe stages. In early AKI, urine output after a furosemide stress test (FST), which involves intravenous administration of furosemide (1.0 or 1.5 mg/kg), can predict the development of stage 3 AKI. We measured several AKI biomarkers in our previously published cohort of 77 patients with early AKI who received an FST and evaluated the ability of FST urine output and biomarkers to predict the development of stage 3 AKI (n=25 [32.5%]), receipt of RRT (n=11 [14.2%]), or inpatient mortality (n=16 [20.7%]). With an area under the curve (AUC)±SEM of 0.87±0.09 (P<0.0001), 2-hour urine output after FST was significantly better than each urinary biomarker tested in predicting progression to stage 3 (P<0.05). FST urine output was the only biomarker to significantly predict RRT (0.86±0.08; P=0.001). Regardless of the end point, combining FST urine output with individual biomarkers using logistic regression did not significantly improve risk stratification (ΔAUC, P>0.10 for all). When FST urine output was assessed in patients with increased biomarker levels, the AUC for progression to stage 3 improved to 0.90±0.06 and the AUC for receipt of RRT improved to 0.91±0.08. Overall, in the setting of early AKI, FST urine output outperformed biochemical biomarkers for prediction of progressive AKI, need for RRT, and inpatient mortality. Using a FST in patients with increased biomarker levels improves risk stratification, although further research is needed.
Copyright © 2015 by the American Society of Nephrology.
0 Communities
1 Members
0 Resources
25 MeSH Terms
Classifying AKI by Urine Output versus Serum Creatinine Level.
Kellum JA, Sileanu FE, Murugan R, Lucko N, Shaw AD, Clermont G
(2015) J Am Soc Nephrol 26: 2231-8
MeSH Terms: Acute Kidney Injury, Adult, Aged, Creatinine, Databases, Factual, Electronic Health Records, Female, Hospital Mortality, Humans, Male, Middle Aged, Renal Replacement Therapy, Severity of Illness Index, Survival Rate, Time Factors, Urine
Show Abstract · Added October 20, 2015
Severity of AKI is determined by the magnitude of increase in serum creatinine level or decrease in urine output. However, patients manifesting both oliguria and azotemia and those in which these impairments are persistent are more likely to have worse disease. Thus, we investigated the relationship of AKI severity and duration across creatinine and urine output domains with the risk for RRT and likelihood of renal recovery and survival using a large, academic medical center database of critically ill patients. We analyzed electronic records from 32,045 patients treated between 2000 and 2008, of which 23,866 (74.5%) developed AKI. We classified patients by levels of serum creatinine and/or urine output according to Kidney Disease Improving Global Outcomes staging criteria for AKI. In-hospital mortality and RRT rates increased from 4.3% and 0%, respectively, for no AKI to 51.1% and 55.3%, respectively, when serum creatinine level and urine output both indicated stage 3 AKI. Both short- and long-term outcomes were worse when patients had any stage of AKI defined by both criteria. Duration of AKI was also a significant predictor of long-term outcomes irrespective of severity. We conclude that short- and long-term risk of death or RRT is greatest when patients meet both the serum creatinine level and urine output criteria for AKI and when these abnormalities persist.
Copyright © 2015 by the American Society of Nephrology.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Considerations and challenges in defining optimal iron utilization in hemodialysis.
Charytan DM, Pai AB, Chan CT, Coyne DW, Hung AM, Kovesdy CP, Fishbane S, Dialysis Advisory Group of the American Society of Nephrology
(2015) J Am Soc Nephrol 26: 1238-47
MeSH Terms: Anemia, Iron-Deficiency, Animals, Cross-Sectional Studies, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Administration Schedule, Erythropoietin, Ferritins, Hematinics, Humans, Infusions, Intravenous, Iron Compounds, Kidney Failure, Chronic, Prognosis, Randomized Controlled Trials as Topic, Renal Dialysis, Risk Assessment, Treatment Outcome
Show Abstract · Added January 6, 2015
Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.
Copyright © 2015 by the American Society of Nephrology.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Staying on target with continuous dialysis.
Demirjian S, Fissell WH
(2015) Clin J Am Soc Nephrol 10: 7-8
MeSH Terms: 2,3-Diphosphoglycerate, Acute Kidney Injury, Erythrocytes, Female, Humans, Hypophosphatemia, Male, Renal Replacement Therapy
Added February 22, 2016
0 Communities
1 Members
0 Resources
8 MeSH Terms