Novel Biomarkers of Renal Function

Author: Edgar V Lerma, MD, FACP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Updated: May 17, 2012
Novel Biomarkers of Renal Function
Serum creatinine levels or glomerular filtration rate (GFR), as well as urinary output, are the most commonly used
markers of renal function and are used to determine the magnitude of renal injury.
It must be recognized, however, that such markers are imperfect. They cannot be used to distinguish between
hemodynamically mediated changes in renal function, such as prerenal azotemia as opposed to intrinsic renal failure
or obstructive uropathy. Similarly, changes in volume states can significantly influence the levels of serum creatinine,
further minimizing the true relative change in renal function. Furthermore, there may be a significant time lag (in
hours or days) between the change in the above markers and the actual onset of anatomic or structural damage.
Knowing the above limitations of currently used kidney function markers, it is accepted that they may be unable to
detect any acute injury or process; in fact, their levels may rise coincident with a late period in the injury process.
This has led to research to find more accurate kidney function biomarkers (serum and/or urine).
[1]
Most likely a handful of kidney function biomarkers exist, rather than a single one. It is hoped that such biomarkers,
once identified, will permit early diagnoses, as well as aid in rendering appropriate treatment strategies long before
permanent damage has set in.
Several previously identified moleculesincluding N -acetyl--glucosaminidase,
2
-microglobulin,
1
-microglobulin,
and retinol binding proteinhave led to the discovery of potential biomarkers, such as kidney injury molecule 1
(KIM-1), human neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), cystatin C, clusterin, fatty
acid binding protein, and osteopontin.
Although the discovery of new biomarkers could revolutionize our understanding of acute kidney injury (AKI),
prospective clinical trials will be needed to compare them to each other over a period of many months and to
investigate such factors as their natural tendencies to occur in certain disease states or in periods of high stress and
their occurrence in specific demographics.
Further research (phase 4 clinical trials) will be needed for the development and clinical validation of new biomarkers
for the eventual definition of kidney injury. Such trials will require large cohorts of subjects; some trials are already
under way in government- and industry-sponsored studies.
As these new biomarkers evolve, so will our understanding of AKI. The work of Parikh et al has shown that some of
these biomarkers might enable the distinction between prerenal azotemia, acute tubular necrosis (ATN), and other
glomerular disorders.
[2]
(See Acute Tubular Necrosis for further information on this disorder.)
Ultimately, the goal of biomarker research is the early diagnosis of AKI (within hours, rather than within days or
weeks). In that way, appropriate preventive and preemptive strategies, as well as treatment regimens, can be
rendered at a phase whereby permanent loss of function can be avoided, making AKI truly reversible.
Neutrophil Gelatinase-Associated Lipocalin
The exact physiologic role played in the kidney by NGAL (also called lipocalin - 2 or siderocalin), a 25-kD protein,
remains a mystery. One possibility, however, is that it is involved in renal morphogenesis, such as induction of repair
and reepithelialization. It has been shown to be elevated in the plasma and urine of animal models of ischemic and
nephrotoxic acute kidney injury and, hence, is considered by some to be a novel urinary biomarker for ischemic
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injury.
[3]
The expression of the NGAL messenger ribonucleic acid (mRNA) and protein in the kidney has been shown to be
significantly increased in the kidney tubules of patients with ischemic, septic, or post-transplantation AKI,
[4]
as well as
within 2-6 hours postcardiopulmonary bypass surgery,
[5]
at frequent intervals for 24 hours postcardiopulmonary
bypass surgery in children,
[6]
and even following contrast administration.
[7]
Urinary NGAL expression has been suggested as an early marker of AKI in children, although the results in adults
have been less convincing.
[8]
Using samples from the Translational Research Investigating Biomarker Endpoints in AKI study (TRIBE-AKI),
researchers tried to determine if biomarkers measured at the time of first clinical diagnosis of early AKI after cardiac
surgery can potentially predict AKI severity. Biomarkers such as urinary IL-18, urinary albumin to creatinine ratio
(ACR), and urinary and plasma NGAL were demonstrated to improve risk classification compared with the clinical
model alone, with plasma NGAL performing the best (category-free net reclassification improvement of 0.69, P<
0.0001). The authors concluded that biomarkers measured on the day of AKI diagnosis improve risk stratification and
identify patients at higher risk for progression of AKI and worse patient outcomes.
[9]
Interleukin-18
A candidate biomarker for renal parenchymal injury, the cytokine IL-18 is formed in the proximal tubules and
detected in the urine.
[10]
It has been shown in animal models to exacerbate tubular necrosis; neutralizing antibodies
formed against IL-18 were found to reduce renal injury in mice.
Parikh et al
[2]
determined that patients with acute tubular necrosis (ATN) had significantly higher levels of IL-18 in
their urine than did control subjects or persons with other forms of kidney disease. On the other hand, patients with
delayed graft function during the immediate post-transplantation period had higher urinary levels of IL-18 than did
patients who had immediate graft function.
After evaluating the potential use of such biomarkers in patients with AKI (postcardiopulmonary bypass), there has
been some suggestion that urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and IL-18 may be
sequential markers; NGAL levels peak within the first 2-4 hours following AKI, while IL-18 peaks at the 12th hour.
Kidney Injury Molecule 1
Another molecule that is upregulated in postischemic injury in the proximal tubule is kidney injury molecule 1
(KIM-1). Urinary KIM-1 has been suggested as another biomarker for the diagnosis of ischemic ATN.
[11]
It has been suggested that high urinary KIM-1 levels may be an independent predictor (versus creatinine clearance,
proteinuria, or donor age) for graft loss in postrenal transplantation patients.
[12]
Cystatin C
Cystatin C is a 13-kD cysteine protease inhibitor that has gained popularity as an alternative to serum creatinine in
the measurement of renal function of the glomerular filtration rate (GFR). In contrast to the 3 previously discussed
biomarkers, however, serum cystatin C levels are usually noted when the tissue injury has led to significant changes
in the kidneys filtration function or capability. This is the same drawback that is encountered with serum creatinine.
Sodium/Hydrogen Exchanger Isoform 3
Sodium/hydrogen exchanger isoform 3 (NHE3) is the most abundant apical membrane sodium transporter in the
proximal tubules. Believed to be shed into the urine after tubular injury, it is analogous to serum troponins after
cardiac muscle injury.
In one study, it was shown that urinary NHE3 proved to be a better gauge than did the time-honored fractional
excretion of sodium (FENa) in distinguishing prerenal versus intrinsic kidney failure. A clinical assay is yet waiting to
be developed and tested (the current NHE3 assay being particularly cumbersome, requiring ultracentrifugation and
Western blot analysis).
[13]
Contributor Information and Disclosures
Novel Biomarkers of Renal Function http://emedicine.medscape.com/article/1925619-overview
2 of 4 18/07/2014 07:00
Author
Edgar V Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine, Section of Nephrology,
Department of Medicine, University of Illinois at Chicago College of Medicine; Research Director, Internal
Medicine Training Program, Advocate Christ Medical Center; Consulting Staff, Associates in Nephrology, SC
Edgar V Lerma, MD, FACP, FASN, FAHA is a member of the following medical societies: American Heart
Association, American Medical Association, American Society of Hypertension, American Society of Nephrology,
Chicago Medical Society, Illinois State Medical Society, National Kidney Foundation, and Society of General
Internal Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Mahendra Agraharkar, MD, MBBS, FACP, FASN Clinical Associate Professor of Medicine, Baylor College of
Medicine; President and CEO, Space City Associates of Nephrology
Mahendra Agraharkar, MD, MBBS, FACP, FASN is a member of the following medical societies: American
College of Physicians, American Society of Nephrology, and National Kidney Foundation
Disclosure: South Shore DaVita Dialysis Center Ownership interest/Medical Directorship Other; Space City
Dialysis /American Renal Associates Ownership/Medical Directorship Same; US Renal Care Ownership interest
Other
Brent Kelly MD, Assistant Professor, Department of Dermatology, University of Texas Medical Branch,
Galveston, Texas
Brent Kelly is a member of the following medical societies: Alpha Omega Alpha and American Medical
Association
Disclosure: Nothing to disclose.
Chief Editor
Vecihi Batuman, MD, FACP, FASN Professor of Medicine, Section of Nephrology-Hypertension, Tulane
University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of
Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of
Nephrology
Disclosure: Nothing to disclose.
Additional Contributors
George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of
Nephrology, Kidney Disease Program, University of Louisville School of Medicine
George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research,
American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation
Disclosure: Nothing to disclose.
F John Gennari, MD Associate Chair for Academic Affairs, Robert F and Genevieve B Patrick Professor,
Department of Medicine, University of Vermont College of Medicine
F John Gennari, MD is a member of the following medical societies: Alpha Omega Alpha, American College of
Physicians-American Society of Internal Medicine, American Federation for Medical Research, American Heart
Association, American Physiological Society, American Society for Clinical Investigation, American Society of
Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College
of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
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