Finding Improved Markers of Acute Kidney Injury

In the January 2014 Issue of Clinical Laboratory News, published by the AACC (American Association for Clinical Chemistry), one of the cover stories was The Search for Improved Markers of Acute Kidney Injury.

Kidney
The article’s main points are that:

  1. The current markers used to assess acute kidney injury (AKI), creatinine and total urinary protein, are inadequate;
  2. AKI is a risk factor for chronic kidney disease (CKD); and
  3. Monitoring changes in recently identified urinary AKI biomarkers seem to be more appropriate for detecting early signs of AKI.

The latter is easily achieved by using RayBiotech’s Acute Kidney Injury Panels for Human and Rat or Custom Quantibody Arrays

Problems with Previous AKI Markers

Detection of creatinine in urine and in blood has been a diagnostic tool of medicine for more than 100 years. Urinary creatinine levels are used to determine the estimated glomerular filtration rate (eGFR), a measure of kidney function. Although creatinine is useful to determine the magnitude of AKI, it is neither sensitive enough as an early indicator of AKI, nor useful in determining the underlying cause(s) of kidney injury. Also, it is less accurate for patients with low muscle mass and is subject to dietary changes and abnormalities. Moreover, there is sometimes a delay in the appearance of increased urinary creatinine following AKI.

Elevated protein content in urine (or proteinuria) is considered a sensitive marker of kidney injury and is a good marker for monitoring recovery in patients with AKI and CKD. However, it is not very specific and gives little information as to the source or mechanism of kidney injury. Urinary protein levels can increase due to the use of some non-steroidal anti-inflammatory medications, as well as due to the presence of cancers, lupus or rheumatoid arthritis.

Promising New Biomarkers

Several putative urinary biomarkers have been proposed for AKI, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1) and liver-type fatty acid-binding protein (L-FABP) [1,2]. ). Of these, KIM-1 and NGAL appear to hold the most promise as early AKI biomarkers in clinical applications.

KIM-1 (also known as TIM-1) is a transmembrane tubular protein that is a promising early-stage urinary biomarker of AKI. KIM-1 is extremely attractive as an early marker of AKI, as its expression is undetectable at the gene or protein level in normal kidneys but is rapidly and highly up-regulated in ischemic kidneys and AKI induced by toxins [3,4].

NGAL levels in urine also rise rapidly (within 2–4 hours) following AKI [5], and elevated levels of NGAL may be an independent risk factor for CKD patients [6]. Thus, urinary NGAL levels may help to identity CKD patients that are most likely to experience further deterioration of kidney function. Detection of circulating NGAL has also been suggested as a potential early marker of AKI [7,8].

L-FABP is also excreted rapidly in urine (within 4 hours) and was identified as an independent risk factor for AKI among cardiac bypass surgery patients [9]. Moreover, preoperative levels of urinary L-FABP may be a predictor of potential risk for AKI resulting from cardiac bypass surgery [10].

Need for More Research & Development for Markers of AKI and CKD

The article on kidney injury biomarkers in Clinical Laboratory News underscores the fact that, despite the promise of these markers in detecting AKI, more research is needed. The most obvious reason is that most of these studies of early biomarkers for AKI have been done in relatively small numbers of patients and need to be validated in larger patient populations. Second, many of these studies have considered these putative urinary biomarkers individually, not in combination with other putative markers, which may improve their diagnostic and prognostic capabilities. Also, many of these studies have been done with frozen urine that has been well-stored under tightly controlled conditions… conditions that may be different from the fresh urine used in typical clinical labs that may be held at room temperature (or varying temperatures during transit) for hours before testing.

Importantly, there is mounting evidence that the connection between AKI and the risk of future deterioration of kidney function, manifesting as CKD, may be tighter than previously thought [See also Venkatachalam, et al. Am J Physiol Renal Physiol. 2010;298:F1078-F1094.]. However, the mechanisms and potential biomarkers for the role of the natural history of AKI in CKD have yet to be explored in any detail. Therefore, some investigators have called for studies involving long-term follow-up of AKI patients [11].

Additionally, there is growing realization that CKD may be a major contributing factor in cardiovascular diseases (CVD). As such, finding predictive and prognostic biomarkers of transitions from AKI to CKD and CKD to CVD are unmet needs in clinical applications of urinary and serum/plasma biomarkers for kidney disease.

Tools for Detection of AKI Biomarkers in Urine and Blood

Investigation of other NGAL, KIM-1, L-FABP and other markers potentially useful as early markers of AKI have become a high priority for the US FDA and the European Medicines Agency [12,13]. Additional next-generation biomarkers that have been identified for early AKI include urinary and/or plasma levels of Cystatin C [14], Albumin [15,16], Clusterin [17,18], Trefoil Factor 3 [16], beta-2-microglobulin [18], and Osteopontin [19].

RayBiotech’s Acute Kidney Injury Arrays for Human detect all of the markers mentioned above. These are available as C-Series (membranes), which use chemiluminescent detection, like a Western Blot, G-Series (glass slides), which use fluorescence scanning, like a gene microarray. RayBiotech also has similar arrays for detecting AKI in Rats.

In addition, RayBiotech’s Custom Quantibody Arrays (quantitatitive multiplex ELISA on glass slide), which may be customized to detect the markers of your choice in urine, serum or plasma.

To Order or Receive Technical Assistance with RayBiotech’s Products:
In the U.S. and Canada, call 1-888-494-8555 or contact us at info@raybiotech.com.
In other countries worldwide, please visit: http://www.raybiotech.com/distributors

References:

  1. Han WK, Wagener G, Zhu Y, Wang S, Lee HT. Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery. CJASN. 2009;4(5):873–882. doi:10.2215/CJN.04810908. [link]
  2. Devarajan P. Biomarkers for the early detection of acute kidney injury. Curr Opin Pediatr. 2011;23(2):194–200. doi:10.1097/MOP.0b013e328343f4dd. [link]
  3. Han WK, Bailly V, Abichandani R, Rhadhani R, Bonventre JV. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002;62(1):237–244. doi:10.1046/j.1523-1755.2002.00433.x. [link]
  4. Bonventre JV. Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more. Nephrol Dial Transplant. 2009;24(11):3265–3268. doi:10.1093/ndt/gfp010. [link]
  5. Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. CJASN. 2008;3(3):665–673. doi: 10.2215/​CJN.04010907. [link]
  6. Liu KD, Yang W, Anderson AH, Feldman HI, Demirjian S, et al. Urine neutrophil gelatinase–associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease. Kidney Int. 2013;83:909–914. doi:10.1038/ki.2012.458. [link]
  7. Constantin JM, Futier E, Perbet S, Roszyk L, Lautrette A, et al. Plasma neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: A prospective study. J Crit Care. 2010;25(1):e1–176.e6. doi:10.1016/j.jcrc.2009.05.010. [link]
  8. Cruz DN, de Cal M, Garzotto F, Perazella MA, Lentini P, et al. Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population. J Intensive Care Med. 2010;36(3):444–451. doi:10.1007/s00134-009-1711-1. [link]
  9. Portilla D, Dent C, Sugaya T, Nagothu KK, Kundi I, et al. Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery. Kidney Int. 2008;73:465–472. doi:10.1038/sj.ki.5002721. [link]
  10. Matsui K, Kamijo-Ikemori A, Sugaya T, Yasuda T, Kimura K. Usefulness of urinary biomarkers in early detection of acute kidney injury after cardiac surgery in adults. Circulation J. 2012;76(1):213–220. doi:10.1253/circj.CJ-11-0342. [link]
  11. Schiff H, Lang SM, Fischer R. Long-term outcomes of survivors of ICU acute kidney injury requiring renal replacement therapy: a 10-year prospective cohort study. Clin Kidney J. 2012;5(4):297–302. doi:10.1093/ckj/sfs070. [link]
  12. Carlson TH, Sethi AA. A kidney injury biomarker initiative: biomarker research holds the potential for developing new, more accurate and powerful IVDs. IVD Technology. May 18, 2011. http://www.ivdtechnology.com/article/kidney-injury-biomarker-initiative. Last accessed: February 6, 2014.
  13. Bonventre JV, Vaidya VS, Schmouder R, Feig P, Dieterle F. Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol. 2010;28(5):426–440. doi:10.1038/nbt0510-436. [link]
  14. Koyner JL, Bennett MR, Worcester EM, Ma Q, Raman J, et al. Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery. Kidney Int. 2008;74:1059–1069. doi:10.1038/ki.2008.341. [link].
  15. Bolisetty S, Agarwal A. Urine albumin as a biomarker in acute kidney injury. Am J Physiol Renal Physiol. 2011;300(3):F626–F627. doi:10.1152/ajprenal.00004.2011. [link].
  16. Yu Y, Jin H, Holder D, Ozer JS, Villarreal S, et al. Urinary biomarkers trefoil factor 3 and albumin enable early detection of kidney tubular injury. Nat Biotechnol. 2010;28:470–477. doi:10.1038/nbt.1624. [link].
  17. Vinken P, Starcks S, Barale-Thomas A, Sonee M, et al. Tissue Kim-1 and urinary clusterin as early indicators of cisplatin-induced acute kidney injury in rats. Toxicol Pathol. 2012;40(7):1049–1062. doi:10.1177/0192623312444765. [link].
  18. Dieterle F, Perentes E, Cordier A, Roth ER, Verdes P, et al. Urinary clusterin, cystatin C, beta-2-microglobulin and total protein as markers to detect drug-induced kidney injury. Nat Biotechnol. 2010;28:463–469. doi:10.1038/nbt.1622. [link].
  19. Lorenzen JM, Hafer C, Faulhaber–Walter R, Kümpers P, et al.Osteopontin predicts survival in critically ill patients with acute kidney injury. Nephrol Dial Transplant. 2011;26(2):531–537. doi:10.1093/ndt/gfq498. [link].