Download a potential universal biomarker for acute kidney injury - AJP

Am J Physiol Renal Physiol 294: F729–F730, 2008;
doi:10.1152/ajprenal.00085.2008.
Editorial Focus
Netrin-1: a potential universal biomarker for acute kidney injury
Alexei G. Basnakian1,2
1
Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, and 2Central
Arkansas Veterans Healthcare System, Little Rock, Arkansas
Address for reprint requests and other correspondence: A. G. Basnakian,
Div. of Nephrology, Dept. of Internal Medicine, Univ. of Arkansas for Medical
Sciences, Little Rock, AR 72205 (e-mail: [email protected]).
http://www.ajprenal.org
injury molecule-1 (1), N-acetyl-glucosaminidase (9), cysteinerich protein 61 (6), hepatocyte growth factor (10), meprin A␤
(2), and exosomal fetuin-A (11). Importantly, the mode by
which netrin-1 reacts to AKI differs from all of the previously
known markers. Urinary levels of netrin-1 return back to
normal level during reperfusion, suggesting that it also can be
used as a prognostic marker for renal recovery, which would
significantly increase its clinical value.
Ramesh and coauthors (8) also examined the importance of
netrin-1 as a marker for acute renal failure of various etiologies
in humans. While it was undetectable in urine of healthy
volunteers, the overwhelming majority of patients had dramatically increased urinary netrin-1.
Since netrin-1 already looks like an unusual marker, this
finding not only adds to the list of potential markers but
strengthens the concept that a panel of markers may be the best
solution to predict, diagnose, and monitor the loss of kidney
function. It would be interesting to test whether netrin-1 is a
predictive biomarker for delayed graft function following kidney transplantation, hypotension due to hemodialysis or cardiovascular surgery, and various nephrotoxicant- or sepsisinduced renal injuries. In addition, urinary netrin-1 may be
potentially useful for identifying the type of injured cells and
determining the nephron segment affected by the injury.
It is very likely that netrin-1 is mechanistically linked to
renal injury since its release is so rapid. However, the exact
mechanisms will need to be a subject for further studies.
Ramesh et al. (8) showed that renal injury caused an
elevation of netrin-1 in tubular epithelial cells; however,
netrin-1 mRNA was not induced. Thus the increased urinary
excretion of netrin-1 seems to be caused by an induction of
protein synthesis and the release of presynthesized protein.
The authors suggested that netrin-1 facilitates cell proliferation and regeneration in response to injury and thus may be
a marker of renal recovery. Therefore, it is also very likely
that netrin-1 has the potential of being used as a therapeutic
target to facilitate kidney recovery after injury.
REFERENCES
1. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV.
Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal
proximal tubule injury. Kidney Int 62: 237–244, 2002.
2. Herzog C, Seth R, Shah SV, Kaushal GP. Role of meprin A in renal
tubular epithelial cell injury. Kidney Int 71: 1009 –1018, 2007.
3. Mehlen P, Furne C. Netrin-1: when a neuronal guidance cue turns out
to be a regulator of tumorigenesis. Cell Mol Life Sci 62: 2599 –2616,
2005.
4. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch
J, Devarajan P. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc
Nephrol 14: 2534 –2543, 2003.
5. Molitoris BA, Melnikov VY, Okusa MD, Himmelfarb J. Technology
Insight: biomarker development in acute kidney injury-what can we
anticipate? Nat Clin Pract Nephrol, 2008.
6. Muramatsu Y, Tsujie M, Kohda Y, Pham B, Perantoni AO, Zhao H,
Jo SK, Yuen PS, Craig L, Hu X, Star RA. Early detection of cysteine
F729
Downloaded from http://ajprenal.physiology.org/ by 10.220.33.2 on August 12, 2017
(AKI) is commonly associated with high
mortality and morbidity rates, which strongly depend on the
time of the diagnosis to allow therapeutic interventions. Recent
studies clearly indicate that routine assessments of kidney
function based on serum creatinine and blood urea nitrogen
measurements and a fall in urine output are outdated because
they fail to identify early stages of renal dysfunction and
structural injury (5).
The kidney has a remarkable capacity to withstand insults
for an extended period of time. The sensitivities of individual
renal cells to injury vary depending on their type, position in
the nephron, local vascularization, and the nature of injury. The
resulting kidney injury is a product of the interplay between
cell dysfunction, cell death, proliferation, inflammation, and
recovery. This sequence of events potentially provides time to
diagnose and determine the cause of kidney failure in the event
that sensitive and specific tests for early kidney injury are
available.
In their study, Ramesh and colleagues (8) demonstrated that
netrin-1 can be used as an early biomarker of AKI. Netrin-1 is
a 50- to 75-kDa laminin-like protein that has been previously
recognized as a chemotropic and cell survival factor in nervous
system development with possible roles in neovascularization,
cell adhesion, and tumorigenesis (3). None of the above indicated that netrin-1 could be used as a biomarker of kidney
injury.
According to Ramesh and colleagues (8), netrin-1 is excreted in the urine as early as 1 h after injury and reaches a
dramatic 30- to 40-fold increase by 3 h and a peak by 6 h after
the insult. Netrin-1 excretion preceded by many hours any
increase in blood urea nitrogen and serum creatinine. The
presented data demonstrated that netrin-1 satisfies the requirements, which are usually applied to the AKI biomarkers. Such
biomarkers are expected to appear very early after the injury
and to be sensitive and specific to the kidney. To allow prompt
diagnostics, AKI biomarkers optimally should be detected
using quick and noninvasive procedures.
The authors tested four types of mouse kidney injury models, including ischemia-reperfusion and three toxic impacts:
cisplatin, endotoxin, and folic acid. All of these were shown to
induce netrin-1 excretion. This observation clearly makes netrin-1 a biomarker, which is universal for hypoxic and toxic
renal injury. The universality of netrin-1 excretion suggests it
may be potentially applicable to various types of AKI, including cases with unknown causes of AKI.
The magnitude and the significance of rapid netrin-1 excretion induced by kidney insults make it outstanding among all
known renal injury markers, including previously described
neutrophil gelatinase-associated lipocalin (4), IL-18 (7), kidney
ACUTE KIDNEY INJURY
Editorial Focus
F730
rich protein 61 (CYR61, CCN1) in urine following renal ischemic reperfusion injury. Kidney Int 62: 1601–1610, 2002.
7. Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL. Urinary
interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney
Dis 43: 405– 414, 2004.
8. Reeves WB, Kwon O, Ramesh G. Netrin-1 and kidney injury. II.
Netrin-1 is an early biomarker of acute kidney injury. Am J Physiol Renal
Physiol. doi:10/1152/ajprenal.00507.2007.
9. Trinchieri A, Zanetti G, Tombolini P, Mandressi A, Ruoppolo M,
Tura M, Montanari E, Pisani E. Urinary NAG excretion after anesthe-
sia-free extracorporeal lithotripsy of renal stones: a marker of early tubular
damage. Urol Res 18: 259 –262, 1990.
10. Yoshimura R, Kasai S, Sugimura K, Wada S, Yoshimura N,
Yamamoto K, Kishimoto T. Hepatocyte growth factor: a sensitive
indicator for CsA-induced nephropathy. Transplant Proc 30: 2017–2018,
1998.
11. Zhou H, Pisitkun T, Aponte A, Yuen PS, Hoffert JD, Yasuda H, Hu
X, Chawla L, Shen RF, Knepper MA, Star RA. Exosomal Fetuin-A
identified by proteomics: a novel urinary biomarker for detecting acute
kidney injury. Kidney Int 70: 1847–1857, 2006.
Downloaded from http://ajprenal.physiology.org/ by 10.220.33.2 on August 12, 2017
AJP-Renal Physiol • VOL
294 • APRIL 2008 •
www.ajprenal.org