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Biomarkers of acute kidney injury: time to learn from implementation

Zoltán H Endre

Crit Care Resusc 2021; 23 (2): 137-140

  • Author Details
  • Competing Interests

    Zoltán Endre is Director of the Australian Kidney Biomarker Research Laboratory at the Prince of Wales Hospital.

  • References
    1. Mehta RL, Cerdá J, Burdmann EA, et al. International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet 2015; 385: 2616-43
    2. Susantitaphong P, Cruz D, Cerdá J, et al. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol 2013; 8: 1482-93
    3. Campbell CA, Li L, Kotwal S, et al. Under-detection of acute kidney injury in hospitalised patients: a retrospective, multi-site, longitudinal study. Intern Med J 2020; 50: 307-14
    4. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 2012; 81: 442-8
    5. Bucaloiu ID, Kirchner HL, Norfolk ER, et al. Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury. Kidney Int 2012; 81: 477-85
    6. James MT, Pannu N, Hemmelgarn BR, et al. Derivation and external validation of prediction models for advanced chronic kidney disease following acute kidney injury. JAMA 2017; 318: 1787-97
    7. Succar L, Pianta TJ, Davidson T, et al. Subclinical chronic kidney disease modifies the diagnosis of experimental acute kidney injury. Kidney Int 2017; 92: 680-92
    8. Section 3: prevention and treatment of AKI. Kidney Int Suppl 2012; 2: 37-68
    9. Endre ZH, Pickering JW, Walker RJ. Clearance and beyond: the complementary roles of GFR measurement and injury biomarkers in acute kidney injury (AKI). Am J Physiol Renal Physiol 2011; 301: F697-707
    10. Westhuyzen J, Endre ZH, Reece G, et al. Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrol Dial Transplant 2003; 18: 543-51
    11. Takaki S, Shehabi Y, Pickering JW, et al. Perioperative change in creatinine following cardiac surgery with cardiopulmonary bypass is useful in predicting acute kidney injury: a single-centre retrospective cohort study. Interact Cardiovasc Thorac Surg 2015; 21: 465-9
    12. Kellum JA, Chawla LS. Cell-cycle arrest and acute kidney injury: the light and the dark sides. Nephrol Dial Transpl 2016; 31: 16-22
    13. Ronco C, Rizo-Topete L, Serrano-Soto M, Kashani K. Pro: Prevention of acute kidney injury: time for teamwork and new biomarkers. Nephrol Dial Transpl 2017; 32: 408-13
    14. Nickolas TL, Schmidt-Ott KM, Canetta P, et al. Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study. J Am Coll Cardiol 2012; 59: 246-55
    15. Haase M, Devarajan P, Haase-Fielitz A, et al. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury a multicenter pooled analysis of prospective studies. J Am Coll Cardiol 2011; 57: 1752-61
    16. Basu RK, Wong HR, Krawczeski CD, et al. Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney injury after cardiac surgery. J Am Coll Cardiol 2014; 64: 2753-62
    17. Stanski N, Menon S, Goldstein SL, Basu RK. Integration of urinary neutrophil gelatinase-associated lipocalin with serum creatinine delineates acute kidney injury phenotypes in critically ill children. J Crit Care 2019; 53: 1-7
    18. Albert C, Albert A, Kube J, et al. Urinary biomarkers may provide prognostic information for subclinical acute kidney injury after cardiac surgery. J Thorac Cardiovasc Surg 2018; 155: 2441-52
    19. Endre ZH, Kellum JA, Di Somma S, et al. Differential diagnosis of AKI in clinical practice by functional and damage biomarkers: workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference. Contrib Nephrol 2013; 182: 30-44
    20. Murray PT, Mehta RL, Shaw A, et al. Current use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference. Kidney Int 2014; 85: 513-2
    21. Langham RG, Bellomo R, D’Intini V, et al. KHA-CARI guideline: KHA-CARI adaptation of the KDIGO Clinical Practice Guideline for Acute Kidney Injury. Nephrology (Carlton) 2014; 19: 261-5
    22. Albert C, Zapf A, Haase M, et al. Neutrophil gelatinase-associated lipocalin measured on clinical laboratory platforms for the prediction of acute kidney injury and the associated need for dialysis therapy: a systematic review and meta-analysis. Am J Kidney Dis 2020; 76: 826-41
    23. Ronco C. Biomarkers for acute kidney injury: is NGAL ready for clinical use? Crit Care 2014; 18: 680
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Acute kidney injury (AKI) is a major clinical problem in the community and in hospital, with hospital-acquired AKI reported in about 20% of adult and 30% of paediatric admissions. 1, 2 Laboratory creatinine data from New South Wales support these figures: 16.4% of patients and 12.4% of hospitalisations developed AKI over a 5-year period. 3 This study also highlighted the under-reporting of AKI in Australia based on coding of the International Classification of Diseases, tenth revision, Australian modification (ICD‐10‐AM) (1.6% incidence) versus laboratory creatinine-based diagnosis (12.4%). In addition, AKI leads to the development of chronic kidney disease (CKD) in many survivors. 4, 5, 6 However, the true incidence of kidney damage following AKI may be even greater, since overt or subclinical AKI may lead to subclinical CKD, which in turn may precede overt CKD. 7 Without measuring renal reserve or performing renal biopsy, subclinical CKD remains undetected, as creatinine remains normal by definition. Along with overt CKD, subclinical CKD remains a risk factor for AKI following repeated kidney exposure to injury. 7 Unfortunately, an inevitable delay in diagnosis is inherent in the functional definition of AKI as recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. 8 This delay results from creatinine kinetics, 9 with the result that creatinine-based diagnosis has never and will never lead to successful intervention trials in AKI. However, this definition is likely to change because of the recognition that kidney damage biomarkers offer near real-time detection of kidney cellular injury.
Several biomarkers have been shown to detect AKI from hours to days earlier than serum creatinine. These include previously recognised proximal tubular proteins, such as enzymes released from damaged epithelial cells (eg, γ-glutamyl transpeptidase [GGT]) 10 to more novel proteins upregulated by injury in kidney epithelial cells (eg, kidney injury molecule 1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) shed into urine, to circulating or filtered markers of inflammation, apoptosis and fibrosis (eg, various microRNA molecules) and filtered markers of cell stress (eg, the cell cycle inhibitors, tissue inhibitor of metalloproteinase 2 [TIMP-2] and insulin-like growth factor-binding protein 7 [IGFBP7]). Such stress or damage biomarkers usually increase before any change in creatinine is measurable 11 and in critical illness, 12 and provide a window of opportunity for early intervention. 13

Recognition that biomarker (BM)-positive/serum creatinine (Cr)-negative subjects have the same risk of subsequent dialysis and death as subjects in whom creatinine alone is increased has led to the recognition that BM+/Cr− subjects have (by a creatinine-based definition) a subclinical category of AKI. 14, 15 Subsequent studies have verified these conclusions in children. 16, 17 Adults with subclinical AKI after cardiac surgery also have increased mortality up to 7 years later. 18

Therefore, the next step in the evolution of the definition of AKI is the incorporation of damage biomarkers into the day-to-day definition of AKI used in clinical practice. The simplest step is a matrix of four categories: no AKI (BM−/Cr−), subclinical AKI (BM+/Cr−), perfusion-dependent AKI (BM−/Cr+), and severe AKI (BM+/Cr+). 19, 20 As expected, the severe category is associated with more severe outcomes, 15 and combining functional and damage biomarkers improved diagnostic precision. 16 However, wider implementation outside a research setting has awaited validation of appropriate biomarker thresholds for each novel damage biomarker in a range of relevant clinical AKI contexts. 21

Biomarker thresholds have now been validated in global studies for NGAL 22 and several have been approved and entered regular clinical practice: NGAL in Europe, 23 [TIMP-2]∙[IGFBP7] (marketed as NephroCheck, Biomérieux) in the United States 24 and Europe, 25 and liver-type fatty acid-binding protein (L-FABP) in Japan. 26 NephroCheck received approval from the US Food and Drug Administration for early diagnosis and prediction of progression to more severe AKI. 24 These observations suggest that these biomarkers are ready for inclusion in clinical practice. For example, triaging with urinary [TIMP-2]∙[IGFBP7] immediately after cardiopulmonary bypass has led to simple and successful intervention by targeted application of KDIGO guidelines, with 33% and 35% reductions in moderate (Stage 2) and severe (Stage 3) AKI respectively. 27 Similar benefits were obtained by implementing a KDIGO-recommended intervention after triaging with urinary [TIMP-2]∙[IGFBP7] following major non-cardiac surgery, achieving a 66% reduction in Stage 2 and Stage 3 AKI as well as a 5-day reduction in length of stay and associated health care costs. 28
Combining damage biomarkers with functional biomarkers also improves diagnostic precision and management of AKI. For example, in children after cardiopulmonary bypass using plasma cystatin C (pCysC) as the functional biomarker and urinary NGAL (uNGAL) as the damage biomarker, the composite uNGAL+/pCysC+ demonstrated a greater likelihood than an increase in creatinine for severe AKI (Stage 2/3) and for persistent AKI (lasting > 48 hours). 16
However, some refinements were needed to align such a combined function-damage biomarker definition with the three consensus severity stages agreed under the current KDIGO umbrella. Appropriate alignments were proposed at the 23rd Acute Dialysis Quality Initiative (ADQI) meeting in 2019 ( 29 wherein each functional AKI stage is subclassified into BM+ and BM− stages (Figure 1 and Figure 2).

Other subphenotypes (also called endophenotypes) may be definable based on the particular biomarker and clinical scenario. 30
What is lacking now is the widespread dissemination of both information and practice in the clinical arena. It is easy to highlight that much more research is needed. This comes with the territory of introducing new methodologies. However, the time is ripe to introduce biomarkers into hospital clinical practice. A guided and restricted scenario experience will familiarise clinicians with the appropriate use of kidney damage biomarkers, while containing unnecessary costs. This approach is exactly the way the use of creatinine kinase and, subsequently, troponins have facilitated both better biomarkers and better biomarker utilisation in diagnosis and management of myocardial infarction.
Therefore, we recommend initial implementation of biomarkers in high risk settings while clinical familiarity increases. Ideally, a panel of biomarkers should be used, wherein biomarkers with different time courses and mechanisms of release are present, so that the performance of individual biomarkers can be evaluated in different clinical contexts. Realistically, NGAL and [TIMP-2]∙[IGFBP7] should constitute such a panel until more validated biomarkers for hospital laboratory platforms are commercially available. These should be adequate for initial clinical experience in major high risk settings, as these two biomarkers have distinct profiles. [TIMP-2]∙[IGFBP7] is a stress biomarker with a relatively short duration of increase after an injury, while longer and continuing damage will increase both urinary and plasma NGAL. In addition, the already available AKI biomarkers of urinary albumin and urine microscopy for casts would complement this AKI panel.
However, there is a caveat: damage biomarkers are imperfect, just like serum creatinine. Both are an “aid to” rather than a substitute for clinical judgement. Nevertheless, only through hands-on clinical experience in realistic clinical settings will damage biomarkers begin to enhance clinical practice in the same way that the evolution of cardiac injury biomarkers has led to earlier diagnosis of myocardial infarction, early and successful intervention and, through greater awareness of need, to even better biomarkers.