Kidney News April 6#4 : Page 1

April 2014 | Vol. 6, Number 4 New Biomarkers Offer Hope for Identifying Acute Kidney Injury Risk By Eric Seaborg their actual clinical utility, but the find-ings reflect an intense effort to bring some AKI biomarkers to market—with some experts expecting a test to be avail-able in the U.S. sometime this year. At least two assays are available in Europe, and researchers eagerly await data on their effective-ness. AKI is very common among hospitalized patients and leads to increased mortal-ity, with mortality rates ranging from 30 percent to 70 percent, and even higher among those re-quiring dialysis. But the condition continues to vex clinicians because a lack of overt symp-toms makes diagnosis difficult before the loss of organ function. Serum creatinine and urine output remain the leading AKI indicators, but they signal that damage may already be occurring. Even the terminology illustrates the intensified interest in improving care and understanding of this condition. The term AKI replaced acute renal failure in recent years to recognize that the kidney undergoes a spectrum of impairment— and biomarkers could help identify the earliest stages. “This is an effort to stratify patients to identify those who are at the highest risk, separating them from the patients that have a more baseline risk, so treatment resources can be deployed most effec-tively,” said John Kellum, MD, professor of critical care medicine at the University of Pittsburgh and corresponding author for both studies. “There is quite a lot of information on what you should do to try to mitigate the risk of acute kidney injury in patients, but it all begins with identifying patients at high risk.” Kellum and colleagues published a paper last year in Critical Care describing a two-pronged discovery and validation study. The researchers started with more than 1000 potential markers that they narrowed down to about 340 candidates for closer study. They then conducted a Continued on page 2 Inside Journal View Warfaran OK for patients with atrial fibrillation and CKD Home Dialysis Training ASN releases first benchmarks for training nephrology fellows in home dialysis modalities Policy Update President’s proposed 2015 budget gives boost to overall NIH funding, but slims NIDDK funds A relatively new pair of biomarkers may give a valuable early signal of acute kidney injury (AKI), accord-ing to two papers, including a study that selected the pair from a competition with more than 300 potential candidates. Only further research will determine Practice Pointers Find answers to pressing questions about technical challenges in dialysis Industry Spotlight FDA issues tighter standards for presenting information on off-label use of drugs and devices Studies Indicate that Biopsies Do Not Determine Suitability of Organs for Transplantation D eceased-donor kidneys re-trieved for transplantation are increasingly being discarded, and the most common reason given for discarding the kidneys is biopsy results. Two new studies published in the Clinical Journal of the American So-ciety of Nephrology suggest that pro-curement biopsies are not predic-tive of posttransplant outcomes and may only serve to dissuade the use of kidneys that are otherwise suitable for transplant. The findings suggest that other methods are needed when weighing whether to transplant a de-ceased-donor kidney. Biopsy-reported acute kidney injury and allograft outcomes Given ever-increasing numbers of patients with end stage renal disease, the medical community has pushed to expand the deceased-donor organ supply. Unfortu-nately, a clear and consistent balance be-tween organ acceptance and discard after procurement has been difficult to achieve given a lack of precise tools to assess donor kidney quality and prognosis. “Kidney researchers are investigating newer, non-invasive tools to assess kid-ney tissue injury, but we need to fully Continued on page 3

New Biomarkers Offer Hope For Identifying Acute Kidney Injury Risk

Eric Seaborg

A relatively new pair of biomarkers may give a valuable early signal of acute kidney injury (AKI), according to two papers, including a study that selected the pair from a competition with more than 300 potential candidates.<br /> <br /> Only further research will determine their actual clinical utility, but the findings reflect an intense effort to bring some AKI biomarkers to market—with some experts expecting a test to be available in the U.S. sometime this year.At least two assays are available in Europe, and researchers eagerly await data on their effectiveness.<br /> <br /> AKI is very common among hospitalized patients and leads to increased mortality, with mortality rates ranging from 30 percent to 70 percent, and even higher among those requiring dialysis.<br /> <br /> But the condition continues to vex clinicians because a lack of overt symptoms makes diagnosis difficult before the loss of organ function. Serum creatinine and urine output remain the leading AKI indicators, but they signal that damage may already be occurring.<br /> <br /> Even the terminology illustrates the intensified interest in improving care and understanding of this condition. The term AKI replaced acute renal failure in recent years to recognize that the kidney undergoes a spectrum of impairment— and biomarkers could help identify the earliest stages.<br /> <br /> “This is an effort to stratify patients to identify those who are at the highest risk, separating them from the patients that have a more baseline risk, so treatment resources can be deployed most effectively,” said John Kellum, MD, professor of critical care medicine at the University of Pittsburgh and corresponding author for both studies. “There is quite a lot of information on what you should do to try to mitigate the risk of acute kidney injury in patients, but it all begins with identifying patients at high risk.” <br /> <br /> Kellum and colleagues published a paper last year in Critical Care describing a two-pronged discovery and validation study. The researchers started with more than 1000 potential markers that they narrowed down to about 340 candidates for closer study. They then conducted a multicenter study of these 340 markers in more than 500 adults, including patients with sepsis, shock, major surgery, and trauma. This study found that the most effective test was for a combination of two markers, insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2).<br /> <br /> Kellum told Kidney News that these two markers were somewhat of a surprise, but on further examination they made sense. Although they are involved in a variety of different pathways, they share one characteristic—they both induce G1 cell cycle arrest, which is considered a key and very early mechanism in AKI.<br /> <br /> “[Cell cycle arrest] is one of the ways that epithelial cells attempt to protect themselves when they are under stress, and the two biomarkers together cover virtually every conceivable stress that an epithelial cell in the kidney might be exposed to,” Kellum said. In a second phase of this Critical Care study, the researchers enrolled 750 adults with critical illness and compared TIMP-2 and IGFBP7 with other known markers, including neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury marker- 1 (KIM-1), interleukin-18 (IL-18), and liver fatty acid-binding protein (L-FABP).The primary end point was the development within 12 hours of sample collection of stage 2 or 3 AKI using Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The TIMP-2/IGFBP-7 combination achieved an area under the receiveroperating characteristics curve (AUC) score of 0.80, whereas none of the other markers achieved an AUC value greater than 0.72. <br /> <br /> A follow-up prospective, multicenter validation study of an immunoassay for the two markers, just published online in the American Journal of Respiratory and Critical Care Medicine, involved 420 critically ill patients. The study tested the ability of urinary TIMP-2/IGFBP7 at a predetermined cutoff to predict the development of moderate to severe AKI within 12 hours of sample collection. Three independent nephrologists judged whether the patients developed AKI. Patients whose levels exceeded the cutoff had seven times the risk of progressing to AKI compared with patients whose levels were below the cutoff.<br /> <br /> But in terms of specificity and absolute risk, only about 25 percent of those with levels above the cutoff progressed to AKI within 12 hours, compared with 4 percent of the patients with levels below the cutoff.<br /> <br /> The study was funded by Astute Medical (San Diego, CA) to gain performance data to submit to the U.S. Food and Drug Administration (FDA) on the company’s NephroCheck immunoassay. Whether the FDA will approve the test, and how long any decision might take, are of course open questions. The FDA accepted data in 2011 from BioPorto on a test for what is probably the most-studied AKI marker— NGAL—with apparently no word yet on any decision. Both the NGAL and the TIMP-2/IGFBP-7 tests are available as easily run immunoassays in Europe, and data on both are just beginning to trickle in.<br /> <br /> Whatever the outcome of these applications, most specialists anticipate that ultimately a panel of biomarkers is likely to be more helpful than a single marker or test, according to Sarah Faubel, MD, associate professor of medicine at the University of Colorado, Denver, and chair of the American Society of Nephrology’s AKI Avisory Group.<br /> <br /> Faubel said that although the studies by Kellum and colleagues were well-thoughtout and examined an important and heterogeneous population, she was not ready to declare the new markers better than or likely to displace the other contenders. But they are likely to provide another potential tool.<br /> <br /> She noted that the study was based on measuring the markers at a single point, within 15 hours of ICU admission, so “the question is, how does this integrate with other time points during the course of AKI, and how does it integrate with other biomarkers . . . [which could] perhaps identify different phases of AKI.” <br /> <br /> Ravindra Mehta, MD, professor of clinical medicine in the division of nephrology at the University of California, San Diego, said that AKI markers fall into two categories, markers of normal function and markers of damage. The TIMP-2/IGFBP7 combination falls into the damage category, and they do seem to stand out in comparison to other markers with their ability to predict the progression to AKI.But he noted that a lot more experience is required before they are likely to be useful in a clinical sense, and whether they will perform outside the study, in clinical practice, is a question only time will answer.<br /> <br /> Researchers and clinicians continue to advance the field of AKI, reaching consensus on defining the condition and establishing best practices for patient care. The best practices recognize the importance of early diagnosis and intervention, which in turn make biomarkers potentially so valuable.As these studies indicate, this quest continues to move forward. “The general anticipation in the community is that sometime in 2014 we will have access to some biomarker,” Mehta said

Studies Indicate That Biopsies Do Not Determine Suitability Of Organs For Transplantation

Deceased-donor kidneys retrieved for transplantation are increasingly being discarded, and the most common reason given for discarding the kidneys is biopsy results.<br /> <br /> Two new studies published in the Clinical Journal of the American Society of Nephrology suggest that procurement biopsies are not predictive of posttransplant outcomes and may only serve to dissuade the use of kidneys that are otherwise suitable for transplant. The findings suggest that other methods are needed when weighing whether to transplant a deceased-donor kidney.<br /> <br /> Biopsy-reported acute kidney injury and allograft outcomes <br /> <br /> Given ever-increasing numbers of patients with end stage renal disease, the medical community has pushed to expand the deceased-donor organ supply. Unfortunately, a clear and consistent balance between organ acceptance and discard after procurement has been difficult to achieve given a lack of precise tools to assess donor kidney quality and prognosis.<br /> <br /> “Kidney researchers are investigating newer, non-invasive tools to assess kidney tissue injury, but we need to fully understand the utility and limitations of our current gold-standard, invasive assessment tool–kidney biopsy,” said Isaac Hall, MD, MS, of Yale University and the Veterans Affairs Medical Center. He and Chirag Parikh, MD, PhD, led a team that looked for associations between biopsy-reported acute kidney injury at the time of organ procurement with subsequent kidney transplant outcomes.<br /> <br /> “We were hoping to expand our knowledge about these associations and explain inconsistent findings in the medical literature by performing the largest multicenter study of its kind to date,” Hall said.<br /> <br /> Between March 2010 and April 2012, the researchers biopsied 651 kidneys (taken from 369 donors through four organ procurement organizations) that were later transplanted into recipients. The team found that biopsy-reported kidney injury was modestly associated with a delay in organ function in the first week after transplantation, but only for a subgroup of donor kidneys already known to be at high risk for this early outcome. The investigators also found that donor kidney biopsies frequently underreported acute kidney injury with substantial variability.<br /> <br /> “Biopsies are listed as the primary reasons for discarding deceased-donor kidneys; however, as they currently relate to reported acute kidney injury, they provide little utility for determining the overall risk of delayed organ function or even premature organ failure,” Parikh said.<br /> <br /> The authors noted that additional studies are needed to determine how biopsies should affect patterns of organ acceptance or rejection and whether newer methods might be better.<br /> <br /> Biopsies of discarded kidneys vs. matched transplanted kidneys <br /> <br /> In another study, Bertram Kasiske, MD, of the Scientific Registry of Transplant Recipients and Hennepin County (MN) Medical Center, and his colleagues compared the results of biopsies from kidneys that were discarded with the results of biopsies from comparable kidneys that were successfully transplanted.<br /> <br /> The researchers compared biopsies of both kidneys from the same donor, when one kidney was transplanted and the other was discarded. The analysis included biopsy reports from 83 kidneys discarded in 2010 due to biopsy findings, 83 contralateral transplanted kidneys from the same donor, and 83 deceased donors randomly matched to cases by donor risk profile.<br /> <br /> “We found that there was a large degree of overlap between the results of biopsies between kidneys discarded and kidneys transplanted, which raised the question of whether these biopsies can predict outcomes accurately enough to use in the decision to discard or transplant a kidney,” Kasiske said. Also, a comparison of two biopsies from the same kidney often demonstrated significant differences.<br /> <br /> The researchers also found that the quality of the biopsies used in acceptance decisions was low. The percentage of glomeruli that were scarred was most often used to decide whether kidneys were discarded or transplanted; however, this value was highly variable, even in biopsies from the same kidney.<br /> <br /> Graft survival at 1 year was 80 percent for kidneys contralateral to discarded kidneys.This compares with graft survival of 92 percent among all deceased-donor transplants in the Scientific Registry of Transplant Recipients. Therefore, many patients may have benefited from kidneys that were discarded. “If the discarded kidneys had been transplanted with the same graft survival as the transplanted kidneys from the opposite side, many patients may have benefited,” Kasiske said. The results question whether routine procurement biopsies result in discarding kidneys that could be acceptable for many of the patients who die waiting for a kidney transplant.<br /> <br /> “A reasonable conclusion from this and other studies is that the widespread practice of routinely obtaining biopsies to aid in deciding to accept or reject a kidney for transplantation should be abandoned, as has been successfully done in Europe,” Kasiske said. “If abandoning this practice is not acceptable in the U.S., then perhaps additional studies could be designed to more precisely determine the benefits and harms of procurement biopsies.” <br /> <br /> “Both of these studies highlight the limitations of using biopsy results as the sole criterion for turning down donor kidneys,” stated Sayeed Khan Malek, MD, of Brigham and Women’s Hospital in an editorial accompanying the two articles. He also expressed concern that because of the intense scrutiny and regulatory oversight of posttransplant outcomes, some low performing centers adopt a risk-averse strategy and refuse donor kidneys presumed to be of high risk owing to poor biopsy findings.<br /> <br /> Malek noted that when biopsy findings are consistent with the clinical evaluation of the donor, they are useful in determining a kidney’s suitability for transplantation.“However, biopsy findings when considered in isolation are of limited value and should be interpreted with caution when making the decision to turn down a potentially transplantable kidney,” he wrote.

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