Legitimizing Acute Kidney Injury: A More Precise Approach in the Making
In 2017, the Division of Nephrology at NewYork-Presbyterian/Columbia University Irving Medical Center was named one of the six recruitment sites for the nationwide Kidney Precision Medicine Project (KPMP) sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). With the purpose of understanding chronic kidney disease and acute kidney injury, the KPMP seeks to make precision medicine possible for kidney diseases. The five-year project, which will unfold in two main phases, has several objectives for the scientists involved:
- to understand the kidney at a detailed cellular and molecular level
- to create a Kidney Tissue Atlas identifying critical cells, regions, and disease pathways
- to identify new markers and treatment targets that make personalized, effective, and safe treatments possible for kidney diseases
“The Kidney Precision Medicine Project is trying to understand the cell types that are specific to kidney injury at the molecular level and that can be targeted in the future with new therapeutic agents.”
— Dr. Krzysztof Kiryluk
Nephrologists Krzysztof Kiryluk, MD, MS, Jonathan M. Barasch, MD, PhD, and Andrew S. Bomback, MD, are leading the Columbia recruitment component of the KPMP cohort of patients with acute kidney injury (AKI). It is a perfect partnering of expertise. Dr. Kiryluk is a physician-scientist with a primary focus on human genetics and genetic susceptibility to different forms of kidney disease. Dr. Barasch is a cell biologist who has been studying the pathogenesis of AKI for many years. And Dr. Bomback is a clinician with specific expertise in performing kidney biopsies. The team also includes Vivette D. D’Agati, MD, Director of Renal Pathology at Columbia, who oversees one of the largest renal pathology laboratories in the country.
“What is becoming clear, albeit still under investigation, is that the national standards for the diagnosis of acute kidney injury (AKI) are not specific enough to be applied to all of our patients, and as a result have obscured our understanding of AKI,” says Dr. Barasch. “Many fields in medicine utilize multiple tools — cellular, functional, and imaging — for the diagnosis and for understanding disease. Nephrology is the only field in medicine to have a single analyte and a single assay test for acute organ injury, namely the serum creatinine test. By definition, a single mode of testing cannot represent the complexity of 21 different cell types in the kidney. The Kidney Precision Medicine Project, which seeks to rethink the process of acute kidney injury on a cell by cell and a gene by gene level, is exactly the cure for our problem.”
“The Kidney Precision Medicine Project is going to take a completely new approach to two problems that have been around forever: chronic kidney disease and acute kidney injury,” adds Dr. Bomback. “These are the two most common conditions that we see in nephrology. Over the last 10 to 20 years, we have done a very good job of identifying these entities. However, we haven’t done a very good job of getting to the core question of why they happen to certain people and not to others. The bigger question is can we identify any specific targets that will enable us to treat patients who have these entities so that we can reverse the process? Currently, if someone is diagnosed with acute kidney injury that is not due to dehydration, medication, an obstruction, or autoimmune related, but rather is the more common form of a global insult to the kidney, we don’t have a definitive treatment. All we can do is provide supportive care.”
“The Columbia project site is concentrating on acute kidney injury,” says Dr. Kiryluk. “This acute form of kidney damage often occurs in hospitalized patients and carries high morbidity and mortality. This means there is an elevated risk of dying if a patient is diagnosed with AKI during hospitalization.”
A Closer Look at AKI
In the February 2011 issue of Nature Medicine, Dr. Barasch and his co-authors reported that the protein, Ngal, is intensely expressed in the urine of animal test models and also in humans with damage to the kidney. “The protein appears in the urine within three hours of the damage,” explains Dr. Barasch. “The rapidity of gene expression of this protein is such that you can see it earlier than the standard markers of kidney damage and it is extremely sensitive to the injury. As a result of the appearance of Ngal in the urine, one can detect damage initiated in the kidney hours or even days before the usual clinical indications alert the physician to the fact that there’s a problem.”
Most kidney injuries are linked to an infection, severe heart failure, or extremely low blood pressure, notes Dr. Barasch, but they also may be associated with toxicity to medications, including chemotherapy, as well as allergic reactions that affect the kidney. “In the setting of any of these circumstances, Ngal rises very quickly and is secreted from the kidney into the urine alerting the physician. In contrast, simple dehydration, mild heart failure, and diuretic use fail to raise the level of Ngal, meaning that the physician can rule out the effect of these states on the kidney after measuring Ngal. We know this both from animal models and from extensive clinical studies in different Emergency Departments led by Thomas Nickolas, MD, MS, and Sumit Mohan, MD, MPH.”
“As a result of the appearance of Ngal in the urine, one can detect damage initiated in the kidney hours or even days before the usual clinical indications alert the physician to the fact that there’s a problem.”
— Dr. Jonathan M. Barasch
While Ngal has been patented as a biomarker and is known worldwide, it is not yet clinically in use in the U.S. while it undergoes further study. “We have conducted several studies on this protein and found that not only does it have the genetics to be expressed very quickly, but it derives from specialized cells within the collecting duct — a part of the kidney that was not known to participate in kidney damage,” explains Dr. Barasch. “This has opened up a new biology as to how kidney cells respond to injurious stimuli. From the data, we have found many new pathways and developed many fresh ideas about the kidney and kidney damage.”
The Conundrum of Creatinine
The implications of these studies are far-reaching and have the potential to refine the diagnosis of acute kidney injury. “Our findings indicate that probably every cell in the kidney responds to damage in unique ways,” says Dr. Barasch. “In comparison, serum creatinine cannot provide etiological information and it changes too slowly to be useful, especially in time-pressured locations, such as the emergency room or postoperatively. Most importantly, Ngal responds to some stimuli but not to other stimuli that also raise serum creatinine.”
In a review of the electronic health records of 3.8 million emergency and intensive care patients at NewYork-Presbyterian using an algorithm designed by Nicholas P. Tatonetti, PhD, Director of Clinical Informatics, Herbert Irving Comprehensive Cancer Center at Columbia, the researchers detected more than 61,000 diagnoses of acute kidney injury as defined by rising creatinine level. Within three days, however, 73 percent of patients with an AKI diagnosis had creatinine levels that returned to normal, suggesting that many of these patients may not have had kidney damage after all.
“The data also showed that patients who have only transient rises in creatinine don’t make the Ngal protein,” says Dr. Barasch. “This all points to the inadequacy of creatinine in identifying acute kidney injury; that as a marker, it is too broad and encompasses entities that are not really an injury to the kidney; and it is too insensitive and too delayed compared to the proteins that the kidney is making. Previous studies have shown that a small but persistent change in creatinine level is a greater predictor of morbidity and mortality than a large, but transient, increase. But because the course of creatinine cannot be known when first seeing a patient, it is possible to deliver a misleading diagnosis. An initial misdiagnosis can lead to delayed or inadequate treatments.”
Enter the Kidney Precision Medicine Project
“To further research in kidney precision medicine, the NIDDK assembled a network of clinical sites to recruit patients to obtain kidney biopsy tissue for next generation interrogation techniques to try to figure out the precise molecular mechanisms of injury,” explains Dr. Kiryluk. “The recruitment sites — three for acute kidney injury and three for chronic kidney disease — essentially form a national clinical referral network for the KPMP.”
“All of the data for individual patients and their samples, both kidney tissue samples and other biospecimens, will be sent to the KPMP Central Hub, which is responsible for data coordination,” continues Dr. Kiryluk. “The Central Hub interacts with all of the clinical sites, harmonizes the data, and then forwards the tissues to five additional sites nationwide, which will perform tissue interrogation. Each of the tissue interrogation sites will apply a different kind of multi-omic method to interrogate kidney tissue, and all of these methods will be combined and compiled in the form of a multidimensional kidney atlas. Additionally, a patient panel is built into the KPMP consortium. The patients participate in our work groups and committees and they provide feedback to us about many different aspects of this study. This is a very complicated consortium structure and a remarkable investment by the NIDDK.”
“The previous studies that we have done are the tip of the iceberg,” says Dr. Barasch. “Now, through the KPMP, we will be able to use human biopsy tissue to really interrogate the gene response in all different kinds of cells in the kidney to get to the bottom of the response. Rather than a singular response of rising creatinine or a specific pathologic assay, we will find that every cell is responding in a stimulus-dependent manner, bringing accuracy or precision to our diagnoses. KPMP will allow cutting-edge genetic and molecular determination of the process of acute kidney injury. This will not only open up the possibility of better diagnostics for each type of injury, whether it’s chemotherapy, a kidney stone, or a response to sepsis, but it will also allow us to identify the pathways that are potentially druggable.”
“The kidney biopsy is an underutilized tool for making the diagnosis of kidney disease,” notes Dr. Kiryluk. “If we want to think about better ways of discovering therapeutic targets and identifying medications and interventions that can prevent kidney disease, we need to go after the kidney tissue. The idea behind KPMP is that we will be able to demonstrate the utility of kidney biopsy for molecular diagnosis, prognostication, and precise subtyping of kidney injury based on molecular mechanisms. The tissue-derived transcriptional information, combined with the analysis of whole genome sequence data for the same patients, will also provide a powerful tool for dissection of potential genetic mechanisms of kidney injury. This could change clinical practice in terms of indications for biopsy, the physician’s willingness to perform a biopsy and, with increasing patient awareness, patients actually asking the physicians to have a biopsy done.”
“What this project will be accomplishing is changing the paradigm of how we approach patients with acute kidney injury,” adds Dr. Bomback. “Now, when a patient presents with one of these mysterious forms of acute kidney injury, instead of basing our management entirely on clinical suspicion and empiric diagnoses, we are going to suggest a kidney biopsy. We’re going to have that kidney biopsy read by our world-class pathologist here, but we’re also going to have some of that tissue sent to scientists around the country who will interrogate that tissue. Then they are going to try and figure out, by using the newer technologies, if there are signals within the tissue that can be identified and that might be amenable to therapy.”
“What this project will be accomplishing is changing the paradigm of how we approach patients with acute kidney injury.”
— Dr. Andrew S. Bomback
Each of the three KPMP recruitment sites for AKI has a goal of accruing 200 patients with acute kidney injury in the first five years. “This is a fairly ambitious target since we will need to convince patients that this is something that they should think about and that it’s worth the risk,” says Dr. Kiryluk. “But these are sick patients; they’re hospitalized and things are not going well for them. So, this is going to be quite challenging. It is one of the reasons the project has an important ethics component. We are asking patients to contribute an extra piece of their kidney tissue during kidney biopsy. And that is not without risk.”
That is why Paul S. Appelbaum, MD, Director of the Division of Law, Ethics, and Psychiatry at Columbia, and an expert in the ethical and legal aspects of precision medicine, is a key member of the KPMP team at Columbia. And that is also why Dr. Kiryluk emphasizes the importance of patient engagement. “We will get feedback directly from patients in terms of what risks they are comfortable with, what they want to get out of the project, and how we can conduct this study in the most ethical way.”
“We’ve really never been able to approach both acute kidney injury and chronic kidney disease from a curative standpoint,” says Dr. Bomback. “We are hoping that someday we can actually use what we’re learning from this study to be able to say to patients, ‘This is the specific reason why this happened to you and we have a therapy that can cure this.’”
Kiryluk K, Bomback AS, Cheng YL, Xu K, Camara PG, Rabadan R, Sims PA, Barasch J. Precision medicine for acute kidney injury (AKI): Redefining AKI by agnostic kidney tissue interrogation and genetics. Seminars in Nephrology. 2018 Jan;38(1):40-51. Review.
Barasch J, Zager R, Bonventre JV. Acute kidney injury: A problem of definition. Lancet. 2017 Feb 25;389(10071):779-81.
Nickolas TL, Schmidt-Ott KM, Canetta P, Forster C, Singer E, Sise M, Elger A, Maarouf O, Sola-Del Valle DA, O’Rourke M, Sherman E, Lee P, Geara A, Imus P, Guddati A, Polland A, Rahman W, Elitok S, Malik N, Giglio J, El-Sayegh S, Devarajan P, Hebbar S, Saggi SJ, Hahn B, Kettritz R, Luft FC, Barasch J. Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: A multicenter prospective cohort study. Journal of the American College of Cardiology. 2012 Jan 17;59(3):246-55.
Paragas N, Qiu A, Zhang Q, Samstein B, Deng SX, Schmidt-Ott KM, Viltard M, Yu W, Forster CS, Gong G, Liu Y, Kulkarni R, Mori K, Kalandadze A, Ratner AJ, Devarajan P, Landry DW, D’Agati V, Lin CS, Barasch J. The Ngal reporter mouse detects the response of the kidney to injury in real time. Nature Medicine. 2011 Feb;17(2):216-22.
Nickolas TL, O’Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N, Buchen C, Khan F, Mori K, Giglio J, Devarajan P, Barasch J. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Annals of Internal Medicine. 2008 Jun 3;148(11):810-19.