Biomarker blues: balancing hope and hype in acute kidney injury

I have the biomarker blues. Despite several million dollars of active research funding this year from the National Institutes of Health and thousands of published articles when searching PubMed for "acute kidney" and "biomarkers," they remain infrequently used by the vast majority of clinicians around the world. Our rallying cries of the early 2010s on biomarkers1McCullough P.A. Bouchard J. Waikar S.S. et al.Implementation of novel biomarkers in the diagnosis, prognosis, and management of acute kidney injury: executive summary from the tenth consensus conference of the acute dialysis quality initiative (ADQI).Contrib Nephrol. 2013; 182: 5-12Crossref PubMed Scopus (100) Google Scholar ("Anything but creatinine!") have failed to dethrone the humble metabolite, which retains its dominance for the diagnosis and monitoring of acute kidney injury (AKI). Are AKI biomarkers (i.e., urine or blood tests to predict AKI, its cause, or its prognosis) a solution to a pressing medical problem, or an innovation desperately in search for an indication? I will cautiously offer the argument that we have failed to articulate compelling, data-driven reasons to order AKI biomarkers. But first, the good news. A recent report from the Acute Disease Quality Initiative Consensus Conference reviewed >65,000 published articles to develop evidence-based recommendations for biomarker use.2Ostermann M. Zarbock A. Goldstein S. et al.Recommendations on acute kidney injury biomarkers from the acute disease quality initiative consensus conference: a consensus statement.JAMA Netw Open. 2020; 3e2019209Crossref PubMed Scopus (296) Google Scholar Biomarkers like kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, interleukin-18, L-FABP (liver-type fatty acid–binding protein), and NephroCheck, to name a few, have been shown to predict AKI and its prognosis (progression/recovery of AKI, future cardiovascular disease, and death). Now, for the bad news. Despite consensus statements, marketing approval of 4 AKI biomarkers around the world,3Kidney Health InitiativeRoadmap for accelerating the development of biomarkers for acute kidney injury.https://khi.asn-online.org/uploads/KHI_Roadmap_for_Accelerating_the_Development_of_Biomarkers_for_AKI_April2022.pdfDate accessed: November 15, 2023Google Scholar and their incorporation into some4Doi K. Nishida O. Shigematsu T. et al.The Japanese clinical practice guideline for acute kidney injury 2016.J Intensive Care. 2018; 6: 48Crossref Scopus (30) Google Scholar (but not all5National Institute for Health and Care ExcellenceAcute kidney injury: prevention, detection and management.https://www.nice.org.uk/guidance/ng148Date accessed: November 15, 2023Google Scholar) AKI practice guidelines, few clinicians are ordering AKI biomarkers. Why? Are we a generation of naysayers who cling stubbornly to old diagnostic tests developed by venerable giants like Thomas Addis and Robert Schrier? Or is the lack of uptake evidence that we have failed to convince our peers that biomarkers add sufficient clinical value? For an AKI biomarker to be valuable, it should: (i) tell the clinician new and reliable information about the patient; (ii) guide clinical decisions and treatment; and (iii) do so in a manner that helps and does not harm the patient. Accurate prognosis, the focus of the vast majority of the biomarker literature in AKI, is important but not sufficient. A useful AKI biomarker has to provide information that materially changes the physician's behavior (e.g., initiate or discontinue dialysis) and translates into better care. On those counts, AKI biomarkers have a long way to go. We can turn to fields outside of nephrology for context and inspiration (Table 1). The value of bedside measurement of brain natriuretic peptide was established by The Breathing Not Properly Trial, a study of 1586 patients presenting to the emergency department with acute dyspnea.6Maisel A.S. Krishnaswamy P. Nowak R.M. et al.Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure.N Engl J Med. 2002; 347: 161-167Crossref PubMed Scopus (2881) Google Scholar Because the treatment of heart failure is highly evidence based and distinct from the treatment of other causes of dyspnea, diagnostic accuracy alone (83.4%) was sufficient to warrant brain natriuretic peptide's eventual acceptance into clinical guidelines. Procalcitonin is an example of a biomarker that has been studied specifically for treatment decisions in biomarker strategy trials. In the Stop Antibiotics on Procalcitonin Guidance Study of 1575 critically ill patients treated with empiric antibiotics, randomization to early discontinuation based on procalcitonin levels (vs. standard of care) reduced antibiotic use and led to a reduction in mortality.7de Jong E. van Oers J.A. Beishuizen A. et al.Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial.Lancet Infect Dis. 2016; 16: 819-827Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar For both brain natriuretic peptide and procalcitonin, the contexts of use have been clearly identified (when, in whom, and why to order the test), and the results are used to guide clinical decisions.Table 1Examples of well-established biomarkers used in the evaluation of acute presentations of common diseasesOrganBiomarkerAnatomic/functional specificityUse in differential diagnosisExamples of diagnostic or treatment implicationsHeartBNP and N-terminal pro-BNPReleased by ventricles in response to volume expansion and pressure overloadHeart failure vs. other causes of dyspneaTherapy for acute heart failure vs. evaluation and treatment of pulmonary emoblismTroponin I and TReleased by injured myocytesAcute myocardial infarction vs. other causes of chest painIn conjunction with electrocardiography, urgent revascularizationLiverAspartate transaminase and alanine transaminaseReleased by injured hepatocytesPattern of abnormalities can be used to differentiate hepatocellular vs. cholestatic patterns of injuryTesting for toxicology, viral hepatitis, ultrasonography with DopplerAlkaline phosphatase, total bilirubinBiliary obstructionUltrasonography to assess liver parenchyma, bile ductsInternational normalized ratioLiver synthetic capacityUsed in risk scores for liver transplantationLungsProcalcitoninSynthesis is upregulated in response to bacterial infectionBacterial vs. viral pneumoniaEarly discontinuation of antibiotics in community-acquired pneumoniaBNP, brain natriuretic peptide. Open table in a new tab BNP, brain natriuretic peptide. There have been 2 notable examples of AKI biomarkers moving beyond prognostic ability and toward concrete clinical decisions: urinary CXC chemokine ligand (CXCL) 9 and NephroCheck (tissue inhibitor of metalloproteinases 2 and insulin-like growth factor–binding protein). After multiple prospective studies showing NephroCheck's performance for AKI prediction, NephroCheck was implemented in PrevAKI, a single-center and subsequent multicenter trial involving biomarker-driven implementation of an AKI prevention strategy in patients undergoing cardiac surgery.8Zarbock A. Kullmar M. Ostermann M. et al.Prevention of cardiac surgery-associated acute kidney injury by implementing the KDIGO guidelines in high-risk patients identified by biomarkers: the PrevAKI-multicenter randomized controlled trial.Anesth Analg. 2021; 133: 292-302Crossref PubMed Scopus (107) Google Scholar,9Meersch M. Schmidt C. Hoffmeier A. et al.Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial.Intensive Care Med. 2017; 43: 1551-1561Crossref PubMed Scopus (565) Google Scholar Patients with high risk, as identified by postoperative biomarkers, were randomized to usual care versus the Kidney Disease: Improving Global Outcomes (KDIGO) Bundle (optimization of volume status and hemodynamics, functional hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention of hyperglycemia). NephroCheck-guided implementation of the KDIGO bundle was successful (nearly 85% adherence vs. 0% in the control arm) but met only 1 of 10 prespecified secondary end points: the occurrence of stage 2 and 3 AKI (null for stage AKI prevention, renal recovery, length of stay, and others). Is the reduction in stage 2 or 3 AKI a game changer for biomarkers in AKI prevention? Although the authors deserve credit for conducting such a study, I would argue no. Importantly, PrevAKI did not test the value of the biomarker. Rather, it tested the value of the KDIGO bundle when applied to high-risk patients as identified by the biomarker. This is a critical difference. A trial design that tests the value of the biomarker and the intervention could look like this (Figure 1)10Hu C. Dignam J.J. Biomarker-driven oncology clinical trials: key design elements, types, features, and practical considerations.JCO Precis Oncol. 2019; 3PO.19.00086Google Scholar: randomize patients to biomarker testing versus no biomarker testing; patients would then receive the intervention (KDIGO bundle) based on the result of NephroCheck versus conventional criteria. The essential analysis is to compare clinical outcomes between the 2 groups. This approximates the counterfactual: would the patient in front of me have been treated differently and better had I known the value of NephroCheck? Urine CXCL9 is another emerging biomarker that addresses an important cause of AKI: acute interstitial nephritis (AIN). In an elegant study involving individuals undergoing for-cause kidney biopsies, urine CXCL9 was found to discriminate between AIN versus acute tubular necrosis (ATN).11Moledina D.G. Obeid W. Smith R.N. et al.Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis.J Clin Invest. 2023; 133e168950Crossref Scopus (7) Google Scholar Urine CXCL9 or another biomarker of inflammation could potentially evolve into a valuable test in differential diagnosis of AKI. Rather than answering a question about risk or prognosis, it answers a question for the clinician to treat the patient: does this person have AIN, and should I act accordingly (i.e., stop a suspected drug; perform a kidney biopsy; or start empiric corticosteroids)? There is appropriate enthusiasm for AIN biomarkers, but a few caveats: the CXCL9 study relied on a small number of samples (41 AIN, 43 ATN, and 153 with other miscellaneous diagnoses, including glomerulonephritis, diabetic kidney disease, and arterionephrosclerosis) and has limited external validity: the patients included in the study had a kidney biopsy for cause, not necessarily to identify ATN versus AIN. The patients in whom an AIN biomarker would be measured in clinical practice are not those who have already undergone biopsy, but rather the much larger number of patients with AKI in whom clinicians are confused and considering the diagnosis of AIN and/or whether to perform biopsy. The diagnostic performance of biomarkers often worsens when testing occurs in other contexts. This study was an essential and informative first step, but more needs to be done in larger numbers of individuals with AKI in whom AIN is on the differential diagnosis before biopsy. Before clinical use, AIN biomarkers should be tested in a randomized controlled biomarker-strategy trial (Figure 1), especially if the context of use includes the decision to perform biopsy and use corticosteroids. An AIN biomarker may identify inflammation with high accuracy, but in a way that ultimately exposes patients to procedural complications from biopsy and/or harm if corticosteroids do not work in certain cases of AIN, despite the inflammation in the biopsy. Only a clinical trial would offer insight into net harms and benefits from the information yield by a biomarker level. Another chemokine, urine CXCL10, has been studied extensively in transplant nephrology for the detection of allograft rejection. Disappointingly, a randomized controlled biomarker-strategy trial of urine CXCL10 to guide allograft biopsy in 241 kidney transplant recipients failed to show an improvement in the primary composite outcome that included graft loss and clinical rejection at 12 months.12Hirt-Minkowski P. Handschin J. Stampf S. et al.Randomized trial to assess the clinical utility of renal allograft monitoring by urine CXCL10 chemokine.J Am Soc Nephrol. 2023; 34: 1456-1469Crossref Scopus (7) Google Scholar That study, performed by Hirt-Minkowski et al., deserves to be considered as a guide for AKI biomarker studies. Among the 120 patients randomized to urine CXCL10-guided biopsy, a total of 70 additional biopsies were performed, leading to new diagnoses of rejection. As a result, additional immunosuppression may have been used because of the biomarker result, and in fact the rates of infection trended higher in the CXCL10 versus control arms. The ultimate value, or harm, of CXCL10 testing therefore has to take into consideration risks (biopsy; potentially excessive immunosuppression) as well as benefits (enhanced identification of treatment-responsive rejection). Selecting among biomarker trial designs is not trivial and requires balancing statistical efficiency, cost, and ethics.10Hu C. Dignam J.J. Biomarker-driven oncology clinical trials: key design elements, types, features, and practical considerations.JCO Precis Oncol. 2019; 3PO.19.00086Google Scholar,13Freidlin B. McShane L.M. Korn E.L. Randomized clinical trials with biomarkers: design issues.J Natl Cancer Inst. 2010; 102: 152-160Crossref PubMed Scopus (294) Google Scholar,14Jacobsen E. Sawhney S. Brazzelli M. et al.Cost-effectiveness and value of information analysis of NephroCheck and NGAL tests compared to standard care for the diagnosis of acute kidney injury.BMC Nephrol. 2021; 22: 399Crossref Scopus (7) Google Scholar As nephrologists, we revel in the ambiguity, subtlety, and art of medicine and differential diagnosis. Many of our patients are incredibly complicated and require the best in clinical and diagnostic reasoning. They also deserve the best in thoughtful biomarker implementation: AKI biomarkers should tell us something we did not know, guide us to do something we might not have otherwise done, and ultimately translate into helping and not harming the patient in front of us. This will require innovative trial designs that ask questions that we are not afraid to answer, even if they point to conventional care instead of the shiniest and newest biomarker. For AKI biomarkers to help our patients, future biomarker studies need to move beyond establishing prognostic significance (about which, as B. B. King lamented, "The thrill is gone…") and toward actionable clinical insights. The author declared no competing interests. Biomarker use in acute kidney injury: are we there yet?Kidney InternationalVol. 105Issue 4PreviewAcute kidney injury (AKI) is an increasingly common disorder with significant heterogeneity. AKI is closely associated with short- and long-term patient outcomes, and its diagnosis and monitoring are critically important. In clinical practice and research studies, this is primarily achieved by serum creatinine concentrations, which have several well-defined limitations. We have witnessed the emergence of novel biomarkers aiming to advance the clinical phenotyping of AKI In the past 2 decades. Despite the abundance of candidate biomarker studies, the utility of these tests has been scrutinized, leading to limited penetration into the clinical settings. Full-Text PDF Are biomarkers in acute kidney injury ready for prime time? The time is right for a second lookKidney InternationalVol. 105Issue 4PreviewSince the early 2000s, the definition of acute kidney injury (AKI) has become sensitive and refined, but the current definition of AKI still has many flaws. Serum creatinine is affected by factors that have no relationship to changes in glomerular filtration rate, for example, changes in creatinine kinetics or muscle mass due to inflammation, medications affecting secretion of creatinine, and hydration. Because of analytic and biological variability, serum creatinine can fluctuate enough to meet the 0.3-mg/dl criterion for AKI without any actual injury. Full-Text PDF