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Acute Kidney Injury (AKI) in all its forms and with all of its causes is a veritable plague among certain populations of patients, such as the critically ill. There are no effective treatments for it once it occurs. Morbidity and mortality are significant components. A prior AKI leaves one susceptible to re-injury and chronic kidney disease, among other complications.
AKI also is bigger than for any one specialty or subspecialty. It is a problem, if it is to be solved, for every group of clinicians that it touches: nephrology, critical care medicine, cardiology, surgery, pharmacy, radiology, heath information technology, and others. The complexity and challenges presented by AKI — the forms it takes, the causes that drive it, the mechanisms that may mitigate or stop its progression — will only be solved by a coordinated and collaborative effort between disciplines.
UPMC has been at the forefront of AKI research and treatment for decades, and numerous advances have occurred in recent years that are helping to drive forward our ability to prevent, diagnose, and treat the condition.
John A. Kellum, MD, professor of critical care medicine and medicine, vice chair of the Department of Critical Care Medicine, and director of the Center for Critical Care Nephrology, is a leader in AKI research and clinical care at UPMC and internationally. While known for his work in AKI, Dr. Kellum’s research and clinical practice span various aspects of critical care medicine, with a focus on sepsis and acute organ dysfunction. At UPMC, he has organized multidisciplinary teams of investigators to study novel approaches to the treatment of sepsis and the understanding of the pathogenesis of AKI. His laboratory integrates the work of epidemiology and health service research with studies of basic mechanisms of disease and new methods of treatment.
Dr. Kellum has been involved in much of the AKI research and clinical program development over many years but is quick to emphasize that the problem is larger than one department and one group of patients, and the global UPMC response to the problem has been an ongoing collaborative effort over many years.
Recent advances in early detection, diagnosis, and clinical tools development are discussed below in this first part of a two-part article. Part two, to be published in Fall 2019, will discuss clinical and translational studies that have shown promise in tackling various aspects of AKI at UPMC and the University of Pittsburgh.
Implementing a Clinical Decision Support System
The successes and advances in AKI research and treatment at UPMC and the University of Pittsburgh are due in no small part to the way leadership in the Renal-Electrolyte Division and Department of Critical Care Medicine have come together to solve a complex problem such as AKI.
“AKI is a problem that requires a coordinated effort across multiple specialties, and I think we have been very successful in making that happen. It shows up in the aspects of the problem that we have tackled, and it shows up in the successes we have had,” says Dr. Kellum.
In 2018, Dr. Kellum and colleagues published findings in the Journal of the American Society of Nephrology analyzing data for three years on the effect of a clinical decision support system (CDSS) in use at UPMC for AKI.1
The computer-assisted decision support tool was designed to derive a baseline serum creatinine level for patients from historical values in the electronic medical record, and then flag changes in the patient’s creatinine and KDIGO stage.
While kidney function is monitored using simple blood tests, subtle changes can elude or delay detection of a problem. Failure to recognize and manage acute kidney injury in the early stages can lead to devastating outcomes for patients and increased costs to the health care system. Benefits of earlier detection of AKI include earlier intervention to mitigate loss of kidney function, and reduced hospital and long-term health care costs as a result of avoiding progression to severe and permanent kidney damage.
In 2013, working with UPMC’s eRecord system, Kellum’s team released a computer program within the electronic health record system across 14 UPMC hospitals. The program monitored levels of blood creatinine, a standard measure of kidney function, over time and analyzed changes in those levels. If the levels rose too high or fast, the program fired an alert in the patient’s electronic health record informing doctors that acute kidney injury could be present. It also helped determine the stage of injury based on changes from the patient’s baseline kidney function.
To determine what effect the computer program had on physician behavior and patient outcomes, Dr. Kellum and his colleagues analyzed records from more than half a million patients admitted to UPMC. They started a year before the alert system was deployed, and continued for two years after. Patients with acute kidney injury had a small yet sustained decrease in hospital mortality of 0.8 percent, 0.3-day shorter length of stay, and a decrease of 2.7 percent in dialysis rates, compared to patients with AKI prior to alert implementation. Even after adjusting for age and severity of illness, these changes remained highly significant.
What the analysis showed was a small, yet important benefit to the use of such a decision tool. In absolute terms, the changes are small, but given the annual frequency of acute kidney injury in hospitalized U.S. patients of about 12 percent — or 2.2 million people — these results would, if generalized to the entire country, translate into more than 17,000 lives and $1.2 billion saved per year.
“We were able to show a number of outcomes with the study, but also continue to paint the picture of AKI as a prevalent disease process, but one in which one small solution to a large problem can chip away at it and make incremental gains. Ultimately that may be the best strategy to effective AKI prevention, detection, and treatment — many small successes each tackling a subset of the larger problem,” says Dr. Kellum.
Efforts in Diagnosis
In 2014, the FDA approved NephroCheck,® the first-ever FDA-approved diagnostic test for acute kidney injury. Dr. Kellum was the lead investigator on the project, and UPMC and the University of Pittsburgh led efforts to discover and validate the biomarkers used in this novel diagnostic tool.
“This was a hugely important step in the battle against AKI. We have been using the test clinically at UPMC since its approval, and we have incorporated it into a variety
of therapeutic bundles, particularly in the intensive care unit.”
The test analyzes two distinct biomarkers of AKI — TIMP2 and IGFBP7 — and is used to assess which patients are at risk for developing AKI while in the hospital.
Collaborations With Clinical Pharmacology
The most common cause of AKI is nephrotoxic medications. Many patients admitted to the hospital or intensive care unit receive multiple nephrotoxic medications, putting them at significant risk for AKI.
Emily Joyce, MD, a pediatric nephrologist at UPMC Children’s Hospital of Pittsburgh, has collaborated extensively with Dr. Kellum on various research projects in AKI. Together they have developed a high-density intensive care patient database of critically ill children that includes data points on more than 12,000 patient encounters over a five-year period, from 2010 to 2014. Dr. Joyce is using the database to understand the associations between the administration of certain medications and AKI to better understand risk stratification, and how the risk of AKI can be minimized in certain medication scenarios. Dr. Joyce’s initial investigations are probing antibiotics and antibiotic combinations associated with AKI in critical illness, particularly the use of the broad-spectrum antibiotic vancomycin — alone, and in combination with other agents including piperacillin and tazobactam.
“We also are looking at this in adults with a number of ongoing collaborations Sandra L. Kane-Gill, PharmD, MS, FCCM, FCCP, from the University of Pittsburgh School of Pharmacy. Clearly, it is a much bigger problem than I think anybody recognized. Efforts to mitigate the impact of these medication-induced AKI events also are underway,” says Dr. Kellum.
BEACON and PRESERVE Trials
The Biomarker Effectiveness Analysis in Contrast Nephropathy (BEACON) study for which Dr. Kellum is a co-investigator is examining contrast-induced acute kidney injury (CIAKI), which is a serious complication occurring in patients with chronic kidney disease who undergo angiography. The ongoing study led by Dr. Raghavan Murugan, in the Department of Critical Care Medicine is a collaboration with the leaders of the PRESERVE trial, Drs. Steve Weisbord and Paul Palevsky from the Renal-Electrolyte Division. The study seeks to address two primary issues. First, early detection of CIAKI after contrast exposure is problematic because a rise in serum creatinine or a decline in urine output occurs over several days, leading to many missed cases. Additionally, early risk stratification for long-term adverse events poses a challenge because existing risk prediction models are only partially viable. Having a biomarker or markers that detect subclinical CIAKI before creatinine levels and also aid in risk stratification will change the primary and secondary prevention strategies for CIAKI.
“The BEACON trial is partly related to understanding for whom the nephrotoxicity from contrast could be anticipated because of their biomarker signature. As a consequence, we are looking at a variety of markers of kidney injury in this investigation,” says Dr. Kellum.
Clinical Guidelines Set for Update
In 2012, Dr. Kellum was co-chair of the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for AKI. In 2019, Dr. Kellum once again will contribute to a new initiative that will update the guidelines.
“Much of the initiatives and work discussed above, and others, will become codified in the new guidelines. In this sense, some of the pioneering work that we have accomplished in AKI at UPMC will become part of the standard therapeutic measures recommended for clinicians globally,” says Dr. Kellum.
For example, he and colleagues across the system, most notably Michael Moritz, MD, clinical director of pediatric nephrology at UPMC Children’s, have been involved in a two-decades-long effort to define optimal fluid therapies for hospitalized patients.
Dr. Moritz’s work on fluid tonicity has led to, among other things, the inclusion of the recommendations for isotonic fluids in the recently released American Academy of Pediatrics (AAP) first-ever clinical practice guidelines2 in the United States for the use of intravenous maintenance fluids in children. The new, evidence-based guidelines are meant, in part, to reduce or prevent as many cases as possible of hyponatremia and its frequently severe morbidities and mortalities. Similarly, Dr. Kellum’s work on chloride concentration in fluids has led to recent large pragmatic studies that have concluded that saline should be avoided in favor of more physiologic isotonic crystalloids.
1 Al-Jaghbeer M, Dealmeida D, Bilderback A, Ambrosino R, Kellum JA. Clinical Decision Support for In-Hospital AKI. J Am Soc Nephrol. February 2018; 29 (2): 654-660.
2 Feld LG, Neuspiel DR, Foster BA, et al. Clinical Practice Guideline: Maintenance Intravenous Fluids in Children. Pediatrics. 2018; 142(6): e20183083. Epub ahead of print.
Wu L, Hu Y, Liu X, Zhang X, Chen W, Yu ASL, Kellum JA, Waitman LR, Liu M. Feature Ranking in Predictive Models for Hospital-Acquired Acute Kidney Injury. Sci Rep. 2018 Nov 23; 8(1): 17298.
Semler MW, Kellum JA. Balanced Crystalloid Solutions. Am J Respir Crit Care Med. 2018 Nov 8. doi: 10.1164/rccm.201809-1677CI. [Epub ahead of print.]
Hoste EAJ, Kellum JA, Selby NM, Zarbock A, Palevsky PM, Bagshaw SM, Goldstein SL,
Cerdá J, Chawla LS. Global Epidemiology and Outcomes of Acute Kidney Injury. Nat Rev Nephrol. 2018 Oct; 14(10): 607-625.
Joyce EL, DeAlmeida DR, Fuhrman DY, Priyanka P, Kellum JA. eResearch in Acute Kidney Injury:
A Primer for Electronic Health Record Research. Nephrol Dial Transplant. 2018 Mar 30.
Fuhrman DY, Kane-Gill S, Goldstein SL, Priyanka P, Kellum JA. Acute Kidney Injury Epidemiology, Risk Factors, and Outcomes in Critically Ill Patients 16-25 Years of Age Treated in an Adult Intensive Care Unit. Ann Intensive Care. 2018
Feb 14; 8(1): 26.
Liu KD, Vijayan A, Rosner MH, Shi J, Chawla LS, Kellum JA. Clinical Adjudication in Acute Kidney Injury Studies: Findings From the Pivotal TIMP-2*IGFBP7 Biomarker Study. Nephrol
Dial Transplant. 2016 Oct; 31(10): 1641-1646.