Under PAR-07-024, Ancillary Studies to Major Ongoing NIDDK and NHLBI Clinical Research Studies NIDDK, we are proposing to conduct a study which aims to examine the natural history of Acute Kidney Injury (AKI) arising in patients with sepsis. Sepsis is found in more than 50% of critically-ill patients with AKI.3 The NIH has recently funded a large therapeutic trial of early septic shock (P50 GM076659). This trial, Protocolized Care for Early Septic Shock (ProCESS), will randomize 1935 patients at 19 centers to three different treatment arms. The opportunity to study patients from the ProCESS cohort presents us with an historic opportunity to prospectively conduct a large natural history study ancillary to an extensive multi-center trial in a setting which is most likely to result in AKI. Our proposal, Protocolized Goal-directed Resuscitation of Septic Shock to Prevent Acute Kidney Injury (ProGReSS AKI), will examine the effect of protocolized resuscitation on the development of AKI. We also seek to explore mechanisms underlying the effect of the intervention and to evaluate markers of renal injury and repair in order to help select patients for future interventional trials. In keeping with the NIH roadmap, in order to understand the clinical utility of this work, we will build a clinical risk prediction model that will consider biomarkers and clinical variables. We have organized these tasks as three specific aims: 1. test the hypothesis that protocolized resuscitation prevents or lessens severity or duration of AKI, 2. determine which pathophysiologic derangements (inflammation, ischemia, oxidative stress, and coagulation/ thrombosis), in combination or individually, are associated with the development of AKI, and 3. determine whether biomarkers can predict AKI and recovery from AKI in the setting of sepsis. Part of our study will include home visits, for which we have opted to separate from the parent trial so as to avoid any loss of enrollment incurred by the ancillary study. We will re-contact ProCESS subjects after discharge from the hospital and follow them at five time points for three years. Through this part of the study, we will determine if protocolized resuscitation is more effective in improving long term outcomes (survival, renal recovery, reduced progression of CKD) in the entire cohort as well as in the subpopulation that has evidence of AKI by biomarkers (biomarker-positive AKI).

Public Health Relevance

The incidence of acute kidney injury (AKI) is estimated at approximately 2000 per million population. This study will examine the effectiveness of the most common treatment (fluids) for the prevention and/or attenuation of AKI resulting from its most common cause (sepsis). To guide future studies, this project will also determine which pathophysiologic derangements are associated with the development of AKI, and determine whether currently available biomarkers can predict AKI and recovery from AKI in the setting of sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083961-04
Application #
8486422
Study Section
Special Emphasis Panel (ZDK1-GRB-R (J3))
Program Officer
Narva, Andrew
Project Start
2010-07-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$574,523
Indirect Cost
$183,527
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ring, Troels; Kellum, John A (2016) Strong Relationships in Acid-Base Chemistry - Modeling Protons Based on Predictable Concentrations of Strong Ions, Total Weak Acid Concentrations, and pCO2. PLoS One 11:e0162872
Zarbock, Alexander; Kellum, John A (2016) Remote Ischemic Preconditioning and Protection of the Kidney--A Novel Therapeutic Option. Crit Care Med 44:607-16
Kellum, John A; Chawla, Lakhmir S; Keener, Christopher et al. (2016) The Effects of Alternative Resuscitation Strategies on Acute Kidney Injury in Patients with Septic Shock. Am J Respir Crit Care Med 193:281-7
Kane-Gill, Sandra L; Sileanu, Florentina E; Murugan, Raghavan et al. (2015) Risk factors for acute kidney injury in older adults with critical illness: a retrospective cohort study. Am J Kidney Dis 65:860-9
Kellum, John A (2015) Diagnostic Criteria for Acute Kidney Injury: Present and Future. Crit Care Clin 31:621-32
Kellum, John A; Sileanu, Florentina E; Murugan, Raghavan et al. (2015) Classifying AKI by Urine Output versus Serum Creatinine Level. J Am Soc Nephrol 26:2231-8
Al-Khafaji, Ali; Elder, Michele; Lebovitz, Daniel J et al. (2015) Protocolized fluid therapy in brain-dead donors: the multicenter randomized MOnIToR trial. Intensive Care Med 41:418-26
Kellum, John A (2015) Persistent Acute Kidney Injury. Crit Care Med 43:1785-6
Sileanu, Florentina E; Murugan, Raghavan; Lucko, Nicole et al. (2015) AKI in low-risk versus high-risk patients in intensive care. Clin J Am Soc Nephrol 10:187-96
Handler, Steven M; Cheung, Pui Wen; Culley, Colleen M et al. (2014) Determining the incidence of drug-associated acute kidney injury in nursing home residents. J Am Med Dir Assoc 15:719-24

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