Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Novel Biomarkers of Renal Function

  • Author: Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Oct 29, 2014
 

Overview

A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological or pathogenic processes, or pharmacologic responses to a therapeutic intervention.[1] At present, serum creatinine, which is used to measure the glomerular filtration rate (GFR), is the most commonly used marker of renal function. Unfortunately, serum creatinine is a delayed and unreliable indicator of acute kidney injury (AKI), for the following reasons:

  • The creatinine level is influenced by multiple non-renal factors, such as age, gender, muscle mass, muscle metabolism, diet, medications, and hydration status
  • In AKI, the serum creatinine level can take several hours or days to reach a new steady state and thus does not reflect the actual decrease in GFR in the acute setting
  • Because of renal reserve, the serum creatinine level may not rise until more than half of the kidney function has been lost
  • An increase in the serum creatinine level represents a delayed indication of a functional change in GFR that lags behind structural changes that occur in the kidney during the early stage of AKI
  • Serum creatinine measurement does not allow differentiation between hemodynamically mediated changes in renal function, such as pre-renal azotemia from intrinsic renal failure or obstructive uropathy

Given the limitations of serum creatinine as a marker of renal function, different urinary and serum proteins; molecules; and, most recently, microRNAs have been rigorously investigated over the past decade as possible biomarkers for early and accurate identification of AKI rather than secondary consequences of injury. (See the Table below.) The primary rationale for these developments is that recognition of AKI allows prompt injury-specific intervention that may avert permanent renal damage.

Table. Renal Biomarkers

Table. (Open Table in a new window)

Biomarker Type Biomarker
Functional marker Serum creatinine



Serum cystatin C



Urine albumin



Up-regulated proteins Neutrophil gelatinase-associated lipocalin (NGAL)



Kidney injury molecule 1 (KIM-1)



Liver-type fatty acid–binding protein (L-FABP)



Interleukin 18 (IL-18)



β-trace protein (BTP)



Asymmetric dimethylarginine (ADMA)



Low-molecular-weight proteins Urine cystatin C
Enzymes N-acetyl-glucosaminidase (NAG)



Glutathione-s-transferase (GST)



Gamma-glutamyl transpeptidase (GGT)



Alanine aminopeptidase (AAP)



Lactate dehydrogenase (LDH)



Adapted from de Geus HR, Betjes MG, Bakker J. Biomarkers for the prediction of acute kidney injury: a narrative review on current status and future challenges. Clin Kidney J. 2012; 5 (2): 102-108.

Next

Characteristics of an Ideal Marker for Kidney Disease

Ideally, biomarkers for kidney injury, especially in the acute setting, should have the following characteristics[24] :

  • Kidney specific and allow discrimination between pre-renal, intrinsic and post-renal causes of kidney injury
  • Able to detect kidney injury early in the course of the disease
  • Able to isolate the cause of kidney injury
  • Specific to particular sites in the kidneys and able to provide information on pathologic changes in the primary location of injury (eg, renal tubules, interstitium, vasculature)
  • Easily, reliably, promptly, and noninvasively measurable
  • Stable in its matrix
  • Inexpensive to measure
Previous
Next

Novel Biomarkers of Acute Kidney Injury

Biomarkers of acute kidney injury (AKI) include the following:

  • Neutrophil gelatinase-associated lipocalin (NGAL)
  • Interleukin-18 (IL-18) [2]
  • Kidney injury molecule 1 (KIM-1)
  • Cystatin C
  • Liver-type fatty acid–binding protein (L-FABP)
  • Urinary insulinlike growth factor–binding protein 7 (IGFBP7)
  • Tissue inhibitor of metalloproteinases–2 (TIMP-2)

Neutrophil Gelatinase-associated Lipocalin

NGAL is a 25-kD protein of the lipocalin family. Elevation of NGAL levels has been documented in the plasma and urine of animal models of ischemic and nephrotoxic acute kidney injury; hence, NGAL is considered to be a novel urinary biomarker for ischemic injury.[3]

In human studies, the expression of the NGAL messenger ribonucleic acid (mRNA) and protein has been shown to be significantly increased in the kidney tubules in the following settings:

  • Ischemic, septic, or post-transplantation AKI [12]
  • Within 2-6 hours after cardiopulmonary bypass surgery [13]
  • At frequent intervals for 24 hours post–cardiopulmonary bypass surgery in children [14]
  • Following contrast administration [15]

NGAL has been thought to reduce injury by inhibiting apoptosis and increasing the normal proliferation of kidney tubule cells. More specifically, NGAL has been reported to up-regulate heme oxygenase-1, which preserves proximal tubule N-cadherin, and subsequently inhibits cell death.[17]

NGAL has been tested in multiple studies of patients at risk for AKI. Using samples from the Translational Research Investigating Biomarker Endpoints in AKI study (TRIBE-AKI), researchers tried to determine whether 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.[7]

Moreover, NGAL has shown some potential to aid in the diagnosis of early acute tubular necrosis (ATN) and differentiate it from pre-renal disease. Paragas et al found that in a mouse strain with a gene for bioluminescence and fluorescence inserted into the NGAL gene, imaging after ischemia reperfusion demonstrated illumination of specific cells of the distal nephron, indicating NGAL production at the site of injury. However, no NGAL illumination was seen following maneuvers that lead to significant pre-renal disease. Thus, NGAL may potentially be useful in differentiating pre-renal disease from ATN.{{Ref 25}

Interleukin-18

A candidate biomarker for renal parenchymal injury, the cytokine IL-18 is formed in the proximal tubules and can be detected in the urine.[2] In animal models, IL-18 has been shown to exacerbate tubular necrosis; neutralizing antibodies formed against IL-18 were found to reduce renal injury in mice.

Parikh et al determined that patients with ATN had significantly higher levels of IL-18 in their urine than did control subjects or persons with other forms of kidney disease.[2] In renal transplant recipients, those 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. Furthermore, patients with ischemia-reperfusion injury, glycerol injection, and cisplatin-induced renal injury have likewise been noted to have elevated levels of this pro-inflammatory cytokine.[10, 11, 12]

Evaluation of the potential use of urinary neutrophil gelatinase–associated lipocalin (NGAL) and IL-18 in patients with AKI (post–cardiopulmonary bypass) has led to the suggestion that the two may be sequential markers: NGAL levels peak within the first 2-4 hours following AKI, while IL-18 peaks at the 12th hour.

A potential limitation of IL-18 is that it may be a more generalized marker of inflammation rather than a specific marker of AKI, particularly in the elderly population, who may have underlying baseline decreased kidney function.

Kidney Injury Molecule 1

KIM-1 is a type 1 transmembrane protein that contains extracellular mucin and immunoglobulin domains.[4] It has low basal expression in the normal kidney but it is up-regulated in post–ischemic injury in the proximal tubule. The extracellular domain of KIM-1 appears in the urine shortly after ischemic injury and can be readily detected by a new KIM-1 urinary dipstick, potentially making it a convenient and readily measured marker of AKI.[9, 26]

Apart from its potential as a biomarker for ATN, may have a role in determining risk for the development of AKI. In a prospective study that included 123 patients undergoing cardiac surgery, preoperative KIM-1, along with alpha glutathione-s-transferase (GST), was able to predict the future development of stage 1 and stage 3 AKI.[22]

Moreover, a study by Ichimura et al demonstrated how KIM-1 is able to specifically recognize apoptotic cell surface–specific epitopes expressed by apoptotic tubular epithelial cells and subsequently phagocytose apopototic bodies and necrotic debris.[14] It has been proposed, therefore, that KIM-1 may play a role in renal remodeling after AKI and may be a target for pharmacological intervention.

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 three 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. In addition, higher cystatin C levels have now been associated with male gender, greater height and weight, and higher lean body mass.[23] These are the same drawbacks that are encountered with serum creatinine.

Liver-type Fatty Acid–Binding Protein

L-FABP is a 14-kD protein that is localized predominantly in the proximal tubule.{{Ref 15} Its level in the urine has been noted to be elevated postoperatively in patients who sustained AKI following cardiac surgery. The L-FABP gene is expressed in the renal cortex and is induced by hypoxia.[17] In renal transplant recipients, urinary L-FABP has been noted to strongly correlate with ischemic time and has thus been proposed to be a marker of renal hypoxia.[17]

Several studies have shown that L-FABP can predict a patient’s susceptibility to AKI and determine the implications of the injury. In a meta-analysis of seven prospective cohort studies, L-FABP was shown to detect AKI and predict the need for renal replacement therapy and in-hospital mortality in hospital-based cohorts of patients at risk of AKI.[18] Further validation of its potential value is needed in large cohort studies.

Urinary Insulinlike Growth Factor–Binding Protein 7 and Tissue Inhibitor of Metalloproteinases–2)

After sepsis or ischemic injury, renal tubular cells enter a brief period of cell cycle arrest, a key mechanism implicated in acute kidney injury.[20] In the Sapphire validation study of more than 700 critically ill patients identified in multicenter cohorts, IGFBP-7 and TIMP-2, two novel biomarkers of AKI, both inducers of G1 cell cycle arrest, have been shown to be predictive of AKI, with areas under the curve (AUCs) of 0.76 and 0.79, respectively. Taken together, urinary TIMP-2 and IGFBP7 levels were significantly superior to all previously described markers of AKI (P < 0.002), none of which achieved an AUC greater than 0.72.{{Ref}

In another study of 50 patients at high risk for AKI who were undergoing cardiac surgery with cardiopulmonary bypass, urinary TIMP-2 and IGFBP7 was shown to be a sensitive and specific biomarker to predict AKI early after surgery and to predict renal recovery.{{Ref 56}

In September 2014, the U.S. Food and Drug Administration (FDA) allowed the marketing of a commercial test, NephroCheck, which detects the presence of IGFBP7 and TIMP-2, to help determine whether certain critically ill hospitalized patients are at risk of developing moderate to severe acute AKI in the 12 hours after testing.[60]

Previous
Next

Biomarkers of Chronic Kidney Disease

Biomarkers of chronic kidney disease (CKD) include the following:

  • β-trace protein (BTP)
  • Neutrophil gelatinase-associated lipocalin (NGAL)
  • Kidney injury molecule 1 (KIM-1)
  • Liver-type fatty acid–binding protein (L-FABP)
  • Asymmetric dimethylarginine (ADMA)

β-Trace Protein

BTP, also known as lipocalin prostaglandin D2 synthase, is a lipocalin glycoprotein that has been studied in the evaluation of kidney function. In a report from the mild to moderate kidney disease (MMKD) study group, BTP provided a reliable risk prediction for CKD progression.[27] In a study of more than 800 African Americans with hypertensive CKD, higher BPT level was strongly associated with progression to end-stage renal disease (ESRD), compared with traditional markers of kidney function such as measured glomerular filtration rate (GFR).[53] Although promising, BTP requires validation in large CKD populations.

Neutrophil Gelatinase-associated Lipocalin

In addition to its potential role in the diagnosis of AKI, NGAL may also be a useful biomarker in patients with CKD. Studies in a strain of mice that develop severe renal lesions upon nephron reduction have shown NGAL to be an active player in kidney disease progression.[28]

In a cross-sectional study of 80 non-diabetic patients with CKD stages 2–4, serum NGAL was found to be elevated in those with the most advanced CKD.{{Ref 29} Moreover, urinary and serum NGAL levels have been noted to be elevated in a wide range of kidney diseases, including IgA nephropathy, autosomal polycystic kidney disease, and diabetic nephropathy.[30, 31]

Kidney Injury Molecule 1

When KIM-1 is expressed in renal epithelial cells of mice, these animals develop spontaneous and progressive interstitial kidney inflammation with fibrosis leading to renal failure with anemia, proteinuria, hyperphosphatemia, hypertension, cardiac hypertrophy, and death—findings that are comparable to progressive kidney disease in humans.[32] Consequently, sustained KIM-1 expression has been proposed to promote kidney fibrosis and provide a mechanistic link between acute and recurrent injury with progressive chronic kidney disease.

In a retrospective study of patients with non-diabetic proteinuric kidney disease, KIM-1 levels in urine were found to be elevated, but subsequently decreased when patients received treatment with angiotensin-converting enzyme inhibitors or a low-sodium diet. Those findings suggest a potential role for KIM-1 as a measure of therapeutic efficacy.[55]

In a recent study of a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted the rate of estimated GFR loss and risk of ESRD during 5-15 years of follow-up, identifying KIM-1 as a marker for CKD and predictor of CKD progression.[54]

Liver-type Fatty Acid–Binding Protein

In a study of 50 patients with CKD, the level of L-FABP in urine correlated with the degree of tubulointerstitial damage and urinary protein excretion.[33] In a prospective study, urinary L-FABP was found to be more sensitive than proteinuria in predicting the progression of CKD.[34] In 165 patients without albuminuria from a cohort of 227 type 1 diabetics, baseline urinary L-FABP predicted the development of micro- and macro-albuminuria, suggesting a potential role in distinguishing patients who may benefit from early preventive therapies.[35]

Asymmetric Dimethylarginine (ADMA)

ADMA is an endogenously generated methylated arginine that reversibly inhibits nitric oxide synthase. If present in increased quantities, ADM results in decreased nitric oxide production, which in turn is associated with endothelial dysfunction and kidney damage.

ADMA has been investigated as a biomarker in CKD and its progression. In a study of early CKD in type 2 diabetics, Hanai et al found that increased plasma levels of ADMA were predictive of the development and progression of nephropathy.[36] A prospective study by Ravani et al in patients with CKD found that plasma ADMA levels were inversely correlated with GFR and predicted progression to ESRD.[37]

Previous
Next

Biomarkers of Nephrotoxicity

Novel biomarkers of nephrotoxicity include the following:

  • N-acetyl-glucosaminidase (NAG)
  • Glutathione-s-transferase (GST)
  • Gamma-glutamyl transpeptidase (GGT)
  • Alanine aminopeptidase (AAP)
  • Lactate dehydrogenase (LDH)
  • Kidney injury molecule 1 (KIIM-1)

N-acetyl-glucosaminidase (NAG)

NAG, which is an enzyme found predominantly in lysosomes of the proximal tubular cells, has reemerged as an important biomarker in recent studies.[38] Multiple experiments have shown that NAG is a sensitive marker of acute ischemic and oxidative stress within the kidney. For example, elevations in urinary concentration of NAG have been demonstrated in mice exposed to gentamicin[39] and in rats exposed to cisplatin[40] or lithium[41] ; in the lithium study, antioxidant treatment attenuated the nephrotoxicity.[41]

Glutathione-s-transferase (GST)

GST represents a family of cytosolic, microsomal, and membrane-bound enzymes. The GST alpha isoform is localized in the proximal tubular cells, whereas the pi isoform is confined to distal tubular cells. Increased levels of GST in the urine after nephrotoxic injury are attributed to leakage from the tubular epithelial cells into the tubular lumen secondary to cell damage.[58]

In two strains of rats, GST alpha exhibits its biomarker potential by detecting the presence of proximal tubular necrosis as early as 48 hours after cisplatin-induced injury.[59] In patients with rheumatoid arthritis, acute tubular injury from methotrexate and disease-modifying anti-rheumatic drugs was excluded by normal activity of GST alpha.[42] KIM-1 and GST alpha proved the most sensitive means of predicting polymyxin-induced nephrotoxicity, outperforming conventional biomarkers such as serum creatinine and blood urea nitrogen.[57]

Gamma-glutamyl Transpeptidase (GGT), Alanine Aminopeptidase (AAP) and Lactate Dehydrogenase (LDH)

GGT, AAP, and LDH are brush border enzymes that are present in the proximal renal tubule and are normally present in urine as a consequence of tubular cell shedding. Following gentamicin treatment in rats, increased levels of AAP and GGT were noted at all time points tested, that is, 4, 7, 10, or 14 days of treatment. The results suggest that increased urine AAP and GGT reflect loss of brush border integrity while an increased urine NAG level is consistent with the autophagic response of the kidney to acute injury.[43]

Vancomycin-induced acute tubular necrosis in rats was associated with dose-dependent renal injury by pathological assessment and increased urinary excretion of AAP, GGT, and LDH. However, of these, LDH was the most sensitive indicator of acute kidney injury and correlated most closely with the extent of acute tubular injury.[44]

Kidney Injury Molecule 1

In a dose-response study in rats, KIM-1 and the KIM-1/hepatitis A viral cellular receptor-1 (KIM-1/Havcr1) were found to be more sensitive markers of acute kidney injury following exposure to nephrotoxic chemicals and drugs than were serum urea and creatinine concentrations. In a time course study, urinary KIM-1 was elevated within 24 hours after exposure to gentamicin, mercury, and chromium and remained elevated through 72 hours. In cases where acute drug exposure caused necrosis of around half of all proximal tubules, urinary KIM-1 levels increased but serum urea and creatinine and urinary NAG activity did not differ from controls, indicating that these were too insensitive to detect tubular injury. (Ref 45)

Previous
Next

Biomarkers of Glomerular Diseases

Novel biomarkers may have a role in detection of the following glomerular disorders:

  • IgA nephropathy
  • Membranous nephropathy
  • Focal segmental glomerulosclerosis (FSGS)

IgA Nephropathy

Serum levels of galactose-deficient (Gd)-IgA1 and glycan-specific antibodies directed against the hinge region of Gd-IgA1 represent the most promising candidate biomarkers for IgA nephropathy.[46] These immune complexes deposit in the glomerular mesangium and induce the mesangioproliferative glomerulonephritis characteristic of IgA nephroapthy.

A lectin-based enzyme-linked immunosorbent assay (ELISA) for circulating Gd-IgA1 demonstrates 90% specificity and 76% sensitivity in the diagnosis of IgA nephropathy and thus appears to be one of the best candidates for a new, noninvasive biomarker.[46] In a recent study from China, higher levels of Gd-IgA1 were shown to be independently associated with a greater risk of deterioration in renal function and thus with a poor prognosis in IgA nephropathy.[47] These observations are promising, but require replication in independent cohorts.

Membranous Nephropathy

In 2009, Beck and colleagues identified the M-type phospholipase A2 receptor (PLA2R), a transmembrane receptor that is highly expressed in glomerular podocytes, as a target podocyte antigen that triggers an antibody response in membranous nephropathy.{{Ref 48} In this study, the levels of anti-PLA2R antibodies, primarily of the IgG4 subclass, were elevated in approximately 60% to 70% of patients with primary membranous nephropathy, and a clear correlation between the antibody titers, clinical disease activity, and response to treatment was been demonstrated.

In contrast, PLA2R antibodies were not found in serum from patients with secondary membranous nephropathy due to lupus or hepatitis B, from those with proteinuric conditions other than membranous nephropathy, or from healthy control individuals. In kidney transplant recipients, anti-PLA2R antibodies could be used to diagnose relapsing membranous nephropathy.[49] Treatment with rituximab has been shown to reduce the antibody titers as well as proteinuria.[50]

Focal Segmental Glomerulosclerosis (FSGS)

Support for the role of soluble urokinase receptor (suPAR) in primary FSGS was provided by the selective expression suPAR in mice.[51] Mice exposed to certain forms of suPAR developed foot process effacement, proteinuria, and FSGS-like glomerulopathy. Experimental data indicate that suPAR acts through binding to the podocyte β3 integrin, one of the principal proteins that anchor podocytes to the glomerular basement membrane. The interaction of suPAR and β3 integrin produces structural changes in podocytes, altering the permeability of the glomerular filtration membrane.[52]

In addition, plasmapheresis, which is commonly used to treat recurrent FSGS following kidney transplantation, has been found to induce remission and decrease both serum suPAR levels and beta3 integrin activity in a subset of patients with recurrent FSGS.

The aforementioned reports raised optimism in the nephrology community that the soluble proteinuria-inducing factor has finally been identified and potential therapy directed to this inducing factor realized. Unfortunately, several subsequent studies arose casting doubts on the usefulness of serum suPAR as a diagnostic biomarker for FSGS and it’s ability to distinguish FSGS from other nephrotic syndrome (e.g. minimal change disease) or primary FSGS from secondary FSGS. (Ref 54, 55, 56)

Previous
 
Contributor Information and Disclosures
Author

Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF Clinical 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, FASH, FNLA, FNKF 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, Society of General Internal Medicine

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Otsuka, Mallinckrodt, ZS Pharma<br/>Author for: UpToDate, ACP Smart Medicine.

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 is a member of the following medical societies: American College of Physicians, American Society of Nephrology, National Kidney Foundation

Disclosure: Received ownership interest/medical directorship from South Shore DaVita Dialysis Center for other; Received ownership/medical directorship from Space City Dialysis /American Renal Associates for same; Received ownership interest from US Renal Care for other.

Brent Kelly, MD Assistant Professor, Department of Dermatology, University of Texas Medical Branch, Galveston, Texas

Brent Kelly, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association

Disclosure: Nothing to disclose.

Judy Ann K Tan, MD Fellow, Department of Nephrology, Mount Sinai Hospital

Judy Ann K Tan, MD is a member of the following medical societies: American College of Physicians, International Society of Nephrology, Renal Physicians Association, Philippine Medical Association, American Telemedicine Association

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, 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, International Society of Nephrology

Disclosure: Nothing to disclose.

Acknowledgements

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

References
  1. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001 Mar. 69(3):89-95. [Medline].

  2. 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. 2004 Mar. 43(3):405-14. [Medline].

  3. Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, et al. Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol. 2004 Dec. 15(12):3073-82. [Medline].

  4. Mishra J, Ma Q, Kelly C, Mitsnefes M, Mori K, Barasch J, et al. Kidney NGAL is a novel early marker of acute injury following transplantation. Pediatr Nephrol. 2006 Jun. 21(6):856-63. [Medline].

  5. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005 Apr 2-8. 365(9466):1231-8. [Medline].

  6. Dent CL, Ma Q, Dastrala S, Bennett M, Mitsnefes MM, Barasch J, et al. Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care. 2007. 11(6):R127. [Medline]. [Full Text].

  7. Koyner JL, Garg AX, Coca SG, Sint K, Thiessen-Philbrook H, Patel UD, et al. Biomarkers predict progression of acute kidney injury after cardiac surgery. J Am Soc Nephrol. 2012 May. 23(5):905-14. [Medline]. [Full Text].

  8. Zhou H, Hewitt SM, Yuen PS, Star RA. Acute Kidney Injury Biomarkers - Needs, Present Status, and Future Promise. Nephrol Self Assess Program. 2006 Mar. 5(2):63-71. [Medline]. [Full Text].

  9. 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. 2002 Jul. 62(1):237-44. [Medline].

  10. Wu H, Craft ML, Wang P, Wyburn KR, Chen G, Ma J, et al. IL-18 contributes to renal damage after ischemia-reperfusion. J Am Soc Nephrol. 2008 Dec. 19(12):2331-41. [Medline]. [Full Text].

  11. Homsi E, Janino P, de Faria JB. Role of caspases on cell death, inflammation, and cell cycle in glycerol-induced acute renal failure. Kidney Int. 2006 Apr. 69(8):1385-92. [Medline].

  12. Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest. 2001 May. 107(9):1145-52. [Medline]. [Full Text].

  13. Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem. 1998 Feb 13. 273(7):4135-42. [Medline].

  14. Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Duffield JS, Bonventre JV. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest. 2008 May. 118(5):1657-68. [Medline]. [Full Text].

  15. Maatman RG, van de Westerlo EM, van Kuppevelt TH, Veerkamp JH. Molecular identification of the liver- and the heart-type fatty acid-binding proteins in human and rat kidney. Use of the reverse transcriptase polymerase chain reaction. Biochem J. 1992 Nov 15. 288 ( Pt 1):285-90. [Medline]. [Full Text].

  16. xxxx.

  17. Yamamoto T, Noiri E, Ono Y, Doi K, Negishi K, Kamijo A, et al. Renal L-type fatty acid--binding protein in acute ischemic injury. J Am Soc Nephrol. 2007 Nov. 18(11):2894-902. [Medline].

  18. Susantitaphong P, Siribamrungwong M, Doi K, Noiri E, Terrin N, Jaber BL. Performance of urinary liver-type fatty acid-binding protein in acute kidney injury: a meta-analysis. Am J Kidney Dis. 2013 Mar. 61(3):430-9. [Medline]. [Full Text].

  19. Susantitaphong P, Siribamrungwong M, Doi K, Noiri E, Terrin N, Jaber BL. Performance of urinary liver-type fatty acid-binding protein in acute kidney injury: a meta-analysis. Am J Kidney Dis. 2013 Mar. 61(3):430-9. [Medline]. [Full Text].

  20. Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest. 2005 Mar. 115(3):610-21. [Medline]. [Full Text].

  21. Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med. 2010 May. 16(5):535-43, 1p following 143. [Medline]. [Full Text].

  22. Koyner JL, Vaidya VS, Bennett MR, Ma Q, Worcester E, Akhter SA, et al. Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol. 2010 Dec. 5(12):2154-65. [Medline]. [Full Text].

  23. Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan GC, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int. 2004 Apr. 65(4):1416-21. [Medline].

  24. Taal W, MD, Chertow G, Marsden P, Skorecki K, Yu A. Brenner and Rector's The Kidney; 2012:1019.

  25. Paragas N, Qiu A, Zhang Q, Samstein B, Deng SX, Schmidt-Ott KM, et al. The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat Med. 2011 Feb. 17(2):216-22. [Medline]. [Full Text].

  26. Vaidya VS, Ford GM, Waikar SS, Wang Y, Clement MB, Ramirez V, et al. A rapid urine test for early detection of kidney injury. Kidney Int. 2009 Jul. 76(1):108-14. [Medline]. [Full Text].

  27. Spanaus KS, Kollerits B, Ritz E, Hersberger M, Kronenberg F, von Eckardstein A. Serum creatinine, cystatin C, and beta-trace protein in diagnostic staging and predicting progression of primary nondiabetic chronic kidney disease. Clin Chem. 2010 May. 56(5):740-9. [Medline].

  28. Viau A, El Karoui K, Laouari D, Burtin M, Nguyen C, Mori K, et al. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J Clin Invest. 2010 Nov. 120(11):4065-76. [Medline]. [Full Text].

  29. Malyszko J, Malyszko JS, Bachorzewska-Gajewska H, Poniatowski B, Dobrzycki S, Mysliwiec M. Neutrophil gelatinase-associated lipocalin is a new and sensitive marker of kidney function in chronic kidney disease patients and renal allograft recipients. Transplant Proc. 2009 Jan-Feb. 41(1):158-61. [Medline].

  30. Ding H, He Y, Li K, Yang J, Li X, Lu R, et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy. Clin Immunol. 2007 May. 123(2):227-34. [Medline].

  31. Bolignano D, Coppolino G, Campo S, Aloisi C, Nicocia G, Frisina N, et al. Neutrophil gelatinase-associated lipocalin in patients with autosomal-dominant polycystic kidney disease. Am J Nephrol. 2007. 27(4):373-8. [Medline].

  32. Humphreys BD, Xu F, Sabbisetti V, Grgic I, Naini SM, Wang N, et al. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest. 2013 Sep 3. 123(9):4023-35. [Medline]. [Full Text].

  33. Kamijo A, Sugaya T, Hikawa A, Okada M, Okumura F, Yamanouchi M, et al. Urinary excretion of fatty acid-binding protein reflects stress overload on the proximal tubules. Am J Pathol. 2004 Oct. 165(4):1243-55. [Medline]. [Full Text].

  34. Kamijo A, Sugaya T, Hikawa A, Yamanouchi M, Hirata Y, Ishimitsu T, et al. Clinical evaluation of urinary excretion of liver-type fatty acid-binding protein as a marker for the monitoring of chronic kidney disease: a multicenter trial. J Lab Clin Med. 2005 Mar. 145(3):125-33. [Medline].

  35. Nielsen SE, Sugaya T, Hovind P, Baba T, Parving HH, Rossing P. Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients. Diabetes Care. 2010 Jun. 33(6):1320-4. [Medline]. [Full Text].

  36. Hanai K, Babazono T, Nyumura I, Toya K, Tanaka N, Tanaka M, et al. Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant. 2009 Jun. 24(6):1884-8. [Medline].

  37. Ravani P, Tripepi G, Malberti F, Testa S, Mallamaci F, Zoccali C. Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach. J Am Soc Nephrol. 2005 Aug. 16(8):2449-55. [Medline].

  38. Ali BH, Al-Moundhri M, Eldin MT, Nemmar A, Al-Siyabi S, Annamalai K. Amelioration of cisplatin-induced nephrotoxicity in rats by tetramethylpyrazine, a major constituent of the Chinese herb Ligusticum wallichi. Exp Biol Med (Maywood). 2008 Jul. 233(7):891-6. [Medline].

  39. Li J, Li QX, Xie XF, Ao Y, Tie CR, Song RJ. Differential roles of dihydropyridine calcium antagonist nifedipine, nitrendipine and amlodipine on gentamicin-induced renal tubular toxicity in rats. Eur J Pharmacol. 2009 Oct 12. 620(1-3):97-104. [Medline].

  40. Ali BH, Al Moundhri MS, Tag Eldin M, Nemmar A, Tanira MO. The ameliorative effect of cysteine prodrug L-2-oxothiazolidine-4-carboxylic acid on cisplatin-induced nephrotoxicity in rats. Fundam Clin Pharmacol. 2007 Oct. 21(5):547-53. [Medline].

  41. Oktem F, Ozguner F, Sulak O, Olgar S, Akturk O, Yilmaz HR, et al. Lithium-induced renal toxicity in rats: protection by a novel antioxidant caffeic acid phenethyl ester. Mol Cell Biochem. 2005 Sep. 277(1-2):109-15. [Medline].

  42. Svendsen KB, Ellingsen T, Bech JN, Pfeiffer-Jensen M, Stengaard-Pedersen K, Pedersen EB. Urinary excretion of alpha-GST and albumin in rheumatoid arthritis patients treated with methotrexate or other DMARDs alone or in combination with NSAIDs. Scand J Rheumatol. 2005. 34(1):34-9. [Medline].

  43. Whiting PH, Brown PA. The relationship between enzymuria and kidney enzyme activities in experimental gentamicin nephrotoxicity. Ren Fail. 1996 Nov. 18(6):899-909. [Medline].

  44. Naghibi B, Ghafghazi T, Hajhashemi V, Talebi A. Vancomycin-induced nephrotoxicity in rats: is enzyme elevation a consistent finding in tubular injury?. J Nephrol. 2007 Jul-Aug. 20(4):482-8. [Medline].

  45. Zhou Y, Vaidya VS, Brown RP, Zhang J, Rosenzweig BA, Thompson KL, et al. Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium. Toxicol Sci. 2008 Jan. 101(1):159-70. [Medline]. [Full Text].

  46. Moldoveanu Z, Wyatt RJ, Lee JY, Tomana M, Julian BA, Mestecky J, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int. 2007 Jun. 71(11):1148-54. [Medline].

  47. Zhao N, Hou P, Lv J, Moldoveanu Z, Li Y, Kiryluk K, et al. The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int. 2012 Oct. 82(7):790-6. [Medline]. [Full Text].

  48. Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009 Jul 2. 361(1):11-21. [Medline]. [Full Text].

  49. Debiec H, Martin L, Jouanneau C, Dautin G, Mesnard L, Rondeau E, et al. Autoantibodies specific for the phospholipase A2 receptor in recurrent and De Novo membranous nephropathy. Am J Transplant. 2011 Oct. 11(10):2144-52. [Medline].

  50. Beck LH Jr, Fervenza FC, Beck DM, Bonegio RG, Malik FA, Erickson SB, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol. 2011 Aug. 22(8):1543-50. [Medline]. [Full Text].

  51. Váradi V, György I, Karmazsin L. Neonatal periventricular leukomalacia: diagnosis and monitoring by real-time ultrasound. Acta Paediatr Hung. 1990. 30(1):43-51. [Medline].

  52. Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ, et al. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol. 2012 Dec. 23(12):2051-9. [Medline]. [Full Text].

  53. Bhavsar NA, Appel LJ, Kusek JW, Contreras G, Bakris G, Coresh J, et al. Comparison of measured GFR, serum creatinine, cystatin C, and beta-trace protein to predict ESRD in African Americans with hypertensive CKD. Am J Kidney Dis. 2011 Dec. 58(6):886-93. [Medline]. [Full Text].

  54. Sabbisetti VS, Waikar SS, Antoine DJ, Smiles A, Wang C, Ravisankar A, et al. Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes. J Am Soc Nephrol. 2014 Oct. 25(10):2177-86. [Medline]. [Full Text].

  55. Waanders F, Vaidya VS, van Goor H, Leuvenink H, Damman K, Hamming I, et al. Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial. Am J Kidney Dis. 2009 Jan. 53(1):16-25. [Medline]. [Full Text].

  56. Meersch M, Schmidt C, Van Aken H, Martens S, Rossaint J, Singbartl K, et al. Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery. PLoS One. 2014. 9(3):e93460. [Medline]. [Full Text].

  57. Keirstead ND, Wagoner MP, Bentley P, Blais M, Brown C, Cheatham L, et al. Early prediction of polymyxin-induced nephrotoxicity with next-generation urinary kidney injury biomarkers. Toxicol Sci. 2014 Feb. 137(2):278-91. [Medline].

  58. Harrison DJ, Kharbanda R, Cunningham DS, McLellan LI, Hayes JD. Distribution of glutathione S-transferase isoenzymes in human kidney: basis for possible markers of renal injury. J Clin Pathol. 1989 Jun. 42(6):624-8. [Medline]. [Full Text].

  59. Gautier JC, Riefke B, Walter J, Kurth P, Mylecraine L, Guilpin V, et al. Evaluation of novel biomarkers of nephrotoxicity in two strains of rat treated with Cisplatin. Toxicol Pathol. 2010 Oct. 38(6):943-56. [Medline].

  60. FDA allows marketing of the first test to assess risk of developing acute kidney injury. US Food and Drug Administration. September 5, 2014. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412910.htm. Accessed: October 19, 2014.

  61. Huang J, Liu G, Zhang YM, Cui Z, Wang F, Liu XJ, et al. Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis. Kidney Int. 2013 Aug. 84(2):366-72. [Medline].

  62. Sinha A, Bajpai J, Saini S, Bhatia D, Gupta A, Puraswani M, et al. Serum-soluble urokinase receptor levels do not distinguish focal segmental glomerulosclerosis from other causes of nephrotic syndrome in children. Kidney Int. 2014 Mar. 85(3):649-58. [Medline].

  63. Meijers B, Maas RJ, Sprangers B, Claes K, Poesen R, Bammens B, et al. The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. Kidney Int. 2014 Mar. 85(3):636-40. [Medline].

 
Previous
Next
 
Table.
Biomarker Type Biomarker
Functional marker Serum creatinine



Serum cystatin C



Urine albumin



Up-regulated proteins Neutrophil gelatinase-associated lipocalin (NGAL)



Kidney injury molecule 1 (KIM-1)



Liver-type fatty acid–binding protein (L-FABP)



Interleukin 18 (IL-18)



β-trace protein (BTP)



Asymmetric dimethylarginine (ADMA)



Low-molecular-weight proteins Urine cystatin C
Enzymes N-acetyl-glucosaminidase (NAG)



Glutathione-s-transferase (GST)



Gamma-glutamyl transpeptidase (GGT)



Alanine aminopeptidase (AAP)



Lactate dehydrogenase (LDH)



Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.