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 Table of Contents  
SYMPOSIUM
Year : 2018  |  Volume : 5  |  Issue : 2  |  Page : 26-29

Biomarkers: Acute kidney injury


1 Senior Professor, In charge Pediatric Intensive care, respiratory medicine and Genetics, PGIMS, Rohtak, India
2 Senior Professor, Medicine and Nephrology Unit Pt B D Sharma, PGIMS, Rohtak, India
3 Deputy Civil Surgeon, Rohtak, Haryana, India

Date of Submission29-Mar-2018
Date of Acceptance12-Apr-2018
Date of Web Publication30-Apr-2018

Correspondence Address:
Kundan Mittal
Senior Professor Pediatrics, Pt B D Sharma, PGIMS, Rohtak Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.21304/2018.0502.00369

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  Abstract 


Biomarkers can be measured objectively and can assess physiological as well as pathological process or pharmacological response or helps in deciding therapeutic intervention or prognostication of disease. Biomarkers can be clinical as well as molecular. Kidney is one of the vital organs of human body and has mainly excretory functions. Acute kidney injury is independent risk factor for morbidity and mortality and early intervention has better prognosis. Defining acute kidney injury is still a big issues and various classifications have been proposed but none is suitable to define or identify sub-acute injury to such a vital organ. Measurement of serum creatinine and urine output have been used in almost all definitions but do not pick up early sub-clinical damage associated with normal serum creatinine and urine output. Recently study of general and novel biomarkers have helped in defining the sub-clinical damage, early therapeutic intervention and prognosis of child with acute kidney injury.

Keywords: Acute Kidney Injury, biomarkers, NGAL, Cystatin C


How to cite this article:
Mittal K, Aggarwal H K, Mittal A. Biomarkers: Acute kidney injury. J Pediatr Crit Care 2018;5:26-9

How to cite this URL:
Mittal K, Aggarwal H K, Mittal A. Biomarkers: Acute kidney injury. J Pediatr Crit Care [serial online] 2018 [cited 2020 Mar 29];5:26-9. Available from: http://www.jpcc.org.in/text.asp?2018/5/2/26/281116



  • Kidney is silent organ and injury has little evidence clinically
  • Kidney injury is pandemic (pan-metabolic, panorgan, pan endocrinal) and outcome is of clinical importance
  • Even sub-clinical damage not classified (non- creatinine acute kidney injury and creatinine acute kidney injury) is also important cause of morbidity and mortality


Acute kidney injury (AKI) previously known as acute renal failure (ARF) is the disruption of normal renal function resulting in accumulation of nitrogenous waste products with fluid and electrolytes disturbances. AKI is potentially reversible and ARF indicates sustained renal injury (renal failure is defined as renal function inadequate to clear the waste products of metabolism despite the absence of or correction of hemodynamic or mechanical causes). Presently AKI is defined on the basis of serum creatinine and urine output but AKI also results in disturbances in water, electrolytes, acid-base homeostasis and endocrine abnormalities. AKI can also occur in patient with chronic kidney disease (CKD). One in five adults and one in three children experience AKI during hospital admission. Two percent of hospitalized patient need dialysis. Various diagnostic criteria have been defined to stage acute kidney injury but none is accurate till date to predict acute kidney injury and prognosticate outcome. The diagnosis of AKI has been traditionally relied on measurements of serum creatinine as a marker of GFR and/or monitoring of urine output. However, serum creatinine is a poor biomarker for AKI and thus there is no consensus AKI definition. Also, serum creatinine value is affected by many factors including age, sex, nutrition, muscle status, medications, and hydration status. More than 30 definitions are published literature defining ARF/AKI Recently focus has shifted to biomarkers in predicting, prognosticating and assessing for renal replacement therapy in AKI. Biomarker is objectively measured and evaluated as an indicator of a physiological and pathological process or pharmacological response to treatment or surrogate end points of in clinical trials. Major categories of biomarkers are clinical, functional markers, upregulated proteins, low molecular weight proteins and enzymes. Ideal biomarker is one which predicts and diagnoses the AKI, type, and location of injury.[1],[2],[3],[4]

Functional markers [5],[6],[7]

Serum creatinine: A degradation product of muscle mass and surrogate of glomerular filtration. Serum creatinine is prone to large fluctuation in critical illnesses.

Serum and urine Cystatin C (CyC): Serum cystatin C is a better marker of GFR than serum creatinine and higher diagnostic value in diagnosis of AKI. But it is not clear whether the value is applicable to all forms of AKI. It is also strong predictor of death compared to serum creatinine. Serum values may be affected by corticosteroids therapy, hyperthyroidism, hypertriglyceridemia, and inflammation. Urinary cystatin-C is better marker of AKI and predictor of poor outcome. Cystatin C is produced constantly by all nucleated cells, excreted by glomerular filtration and completely metabolised by proximal tubules. Various factors influence the plasma interpretation of serum CyC which includes age, sex, height, weight, high level of C-reactive protein, abnormal thyroid function, immunosuppressive therapy and smoking. Serum CyC and creatinine levels at birth and 3 days after birth have been reported to be independent of sex, gestation, birth weight, bilirubin levels, and hydration state. Serum CyC level is increased in congenital renal malformations. NGAL, IL-18, KIM-1, and CyC and reported that they may predict AKI and mortality in very low-birth-weight infants. Normal levels of biomarkers in different studies are given in table below.

Up-regulated proteins:

Neutrophil gelatinase-associated lipocalin (NGAL) : NGAL is a small protein linked to neutrophil gelatinase in specific leukocyte granules. It is also expressed in a variety of epithelial tissues associated with anti-microbial defence. In the normal kidney, only the distal tubules and collecting ducts stain for NGAL expression. Urinary NGAL originates from local production in the distal tubules and collecting ducts. Serum and urinary NGAL shows the potential to be a simple and powerful biomarker able to provide an early (within a few hours) AKI diagnosis, and capable of differentiating between prerenal kidney disease and acute tubular necrosis. Sire of renal biomarkers production are shown in figure below.

Extra renal causes of raised plasma NGAL are;

  • Severe sepsis
  • Severe pancreatitis
  • Pancreatic cancer and gastric cancer
  • Acute coronary artery disease
  • Acute exacerbation of chronic obstructive pulmonary disease


Kidney injury molecule-1 (KIM 1): KIM-1 is localized in the apical membrane of dilated tubules in acute and chronic injury and believed to play a role in regeneration processes after epithelial injury and in the removal of dead cells in the tubular lumen through phagocytosis. A reduction in proteinuria with renin angiotensin aldosterone blockade is accompanied by a reduction in urinary KIM-1 excretion.

Liver fatty acid binding protein: Urinary liver fatty acid binding protein (L-FABP) is undetectable in healthy control urine, which is explained by efficient proximal tubular internalization via megalin-mediated endocytosis. Under ischaemic conditions, tubular L-FABP gene expression is induced; in renal disease, the proximal tubular re-absorption of L-FABP is reduced. Heart type FABP (H-FABP) are markers of distal tubule injury.

Interleukin-18: Urinary interleukin-18 is elevated within 6hours of injury and peak 12-18hours in acute tubular necrosis, prerenal azotaemia, graft rejection, chronic renal insufficiency, urinary tract infection and nephrotic syndrome. It is an early marker of AKI compared to serum creatinine and predictor of mortality.

TIMP-2 and IGFBP7: Tissue inhibitor of metalloproteinases 2 (TIMP2) and insulin-like growth factor-binding protein-7 (IGFBP7) are markers of cellular stress in the early phase of tubular cell injury. Combined used of both improves risk stratification.

Endogenous ouabain (EO): A significant association has been reported of preoperative EO levels with adverse renal outcomes in cardiac surgery patients and with mortality in critically-ill patients.

Low-molecular weight proteins Urinary cystatin C (uCyC): Urinary excretion of CyC specifically reflects tubular damage because systemically produced cystatin C is normally not found in urine. However, recent insights show that urinary CyC excretion is augmented by albuminuria. Elevated levels are predictive of poor outcome.

Tubular enzymes

Alpha-glutathione s-transferase (α-GST) and pi- glutathione s-transferase (π-GST): In urine, these enzymes are normally not present. After injury, a-GST is primarily detected in the proximal cells, whereas p-GST is observed in the distal parts.

Gamma-glutanyl transpeptidase (GGT) and alkaline phosphatase (AP): Both are tubular brush border enzymes and are released into urine when there has been significant damage to the brush border membrane with loss of the microvillus structures.

N-acetyl-b-D-glucosaminidase (NAG): Increased activity suggests injury to its cells but may also reflect increased lysosomal activity without cell disruption.

New potential biomarkers:

Clusterin, osteopontin, intestinal trefoil factor (TFF3), glutathione-S-transferase (GST) and pyruvate kinase M2 have been shown to be associated with the development of drug-induced nephrotoxicity in vitro studies.

Early diagnostic/prognostic markers of AKI (differencing prerenal, renal, and postrenal)

  1. Early detection of kidney injury: Serum NGAL, cystatin C, urine NGAL, IL-18, KIM-1, GST, F-LABP.
  2. Kidney damage: Diagnostic biomarkers (Serum NGAL, Cystatin C), urine (NGAL, KIM-1)
  3. Decrease GFR: Diagnostic biomarkers (Serum creatinine, urea, Cystatin C
  4. Kidney Failure: Prognostic biomarkers are serum NGAL, Cystatin C, creatinine, urea, a1- microglobulin, IL-6, C-reactive protein and urine (NGAL, KIM-1) and guide for RRT.
  5. Death: High titre of peak urinary NGAL, IL-18, KIM-1, LFABP, and albumin was independently associated with a 2.0- to 3.2-fold increased risk for mortality.


Table 1 : Biomarkers Baseline Reference Values from Different Studies

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Figure 1: Source of urinary Biomarkers Production[8]

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  Conclusion: Top


Gold standard for assessing kidney functions is GFR and routine parameters guide to diagnosis of AKI but these may not help. The genomic and proteomic tools of modern science have identified many biomarkers to assess the early kidney injury and thus, more sensitive, affordable, accurate, specific, clinically acceptable biomarkers are need of the hour. Biomarkers in combination may be more sensitive in diagnosis of AKI and deciding RRT. Five of few newer biomarkers are most promising: urine albumin/creatinine ratio (uAlb/uCr), cystatin-C (CysC), neutrophil gelatinase- associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) in diagnosing AKI and RRT therapy.

Source of Funding : Nil

Conflict of Interest: Nil



 
  References Top

1.
Zhi-Yong Peng. The biomarkers for acute kidney injury: A clear road ahead? Journal of International Translation Medicine 2016; 4 (3):95-98.  Back to cited text no. 1
    
2.
Arthur JM, Hill EG, Alge JL et al. Evaluation of 32 urine biomarkers to predict the progression of acute kidney injury after cardiac surgery. Kidney Int 2014; 85:431-8.  Back to cited text no. 2
    
3.
Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a metanalysis. Am J Kidney Dis 2002; 40: 221-6.  Back to cited text no. 3
    
4.
Knight EL, Verhave JC, Spiegelman D. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004; 65: 1416-21.  Back to cited text no. 4
    
5.
Okura T, Jotoku M, Irita J. Association between cystatin C and inflammation in patients with essential hypertension. Clin Exp Nephrol 2010; 14: 584-8.  Back to cited text no. 5
    
6.
Ferguson MA, Vaidya V, Bonventre JV (2008) Biomarkers of nephrotoxic acute kidney injury.Toxicology 245:182-193.  Back to cited text no. 6
    
7.
Moore PK, Hsu RK, Liu KD. Management of Acute Kidney Injury: Core Curriculum 2018. Am J Kidney Dis. 2018 Feb 22. pii: S0272-6386(17)31141 -1. doi: 10.1053/j. ajkd.2017.11.021. [Epub ahead of print]  Back to cited text no. 7
    
8.
Ostermann M, Philips BJ, Forni LG. Clinical review: Biomarkers of acute kidney injury: where are we now? Critical Care 2012, 16:233.  Back to cited text no. 8
    


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