Renal Disease Biomarkers

Reviewed and revised 21 September 2014

OVERVIEW

Acute kidney injury (AKI) is a common problem in the critically ill

  • associated with increased morbidity and mortality
  • incidence increasing
  • all biomarkers to date have differing problems

PROBLEMS WITH CURRENT BIOMARKERS

  • elevate too late
  • associated with only some sorts of renal injury
  • lack significant sensitivity and specificity
  • elevations don’t correlate well with predicting clinically relevant outcomes

CLINICAL ASSESSMENT (URINE OUTPUT)

Advantages

  • reducing urine output and anuria
  • considered clinically relevant and sensitive marker of renal function
  • used as surrogate for end-organ perfusion
  • requires accurate measurement and documentation
  • familiar and universally available

Disadvantages

  • invasive (requires IDC -> trauma, infection)
  • difficult to use in some circumstances (e.g. TURP, haematuria requiring bladder washout)
  • catheter can block
  • oliguria can be caused by other factors (e.d. ADH secretion, DI, diuretics) not related to renal dysfunction
  • non-specific – only about 10% of ICU patients with oliguria for <6h develop AKI

CREATININE CLEARANCE

  • estimates GFR (though this is often not needed clinically)
  • requires 24 hours collection
  • accuracy limited due to creatinine secretion thus overestimates GFR
  • assumes steady state in GFR which may be incorrect
  • has the limitations of creatine measurement

PLASMA CREATININE

Advantages

  • commonly used and available
  • well validated

Disadvantages

  • more a marker of renal function rather than injury
  • production may increase with trauma, fever or immobilization
  • GFR may deteriorate by more than 50% prior to a significant rise in serum creatinine
  • influenced by a number of nonrenal factors: age, race, gender, muscle mass, drug metabolism, protein intake, perioperative fluid administration, hydration
  • 10-40% of renal clearance is due to tubular secretion not filtration
  • injury has usually taken place prior to the rise in creatinine (delayed detection – usually ~24h post-injury; retrospective indicator)
  • assay can be affected by artefact

PLASMA UREA

Advantages

  • simple to measure
  • cheap
  • widely available
  • urea/creatinine ratio has some use in determining type of renal failure (e.g. pre-renal versus renal versus rhabdomyolysis)

Disadvantages

  • not specific for renal function
  • affected by: renal disease, protein intake, catabolic state, volume status, GI bleeding, drug therapy (corticosteroids)
  • 40-50% of filtered urea is reabsorbed
  • takes time to accumulate
  • rate of renal clearance is not constant

NOVEL RENAL BIOMARKERS

Advantages

  • may suggest type of acute kidney injury
  • plasma and urine markers exist
  • can detect AKI earlier than Cr

Disadvantages

  • primarily research tools
  • need validation in appropriate clinical settings
  • cost and poor availability

Plasma and Urinary NGAL

  • NGAL = neutrophil gelatinase-associated lipcalin
  • gene that is maximally induced in a renal ischaemia-reperfusion model
  • synthesized and secreted by tubular cells
  • can be rapidly detected in plasma and urine
  • rapid rise means that it can be used to detect injury
  • endogenous role is unclear ?possible renoprotective role in ischaemic injury
  • shown to correlated well in post cardiac bypass renal injury in paediatrics (not so conclusive in adults)

Plasma and Urinary CYSTATIN-C

  • Cystatin C = small cysteine proteinase inhibitor
  • filtered freely and catabolised entirely by the proximal tubular cells
  • if there is renal damage it appears in urine
  • t ½ = 2 hours
  • mixed results when compared to creatinine

INTERLEUKIN-18 (urine)

  • ischaemia-reperfusion injury of the proximal tubules producers an active form of IL-18
  • it has been shown to accurate predict delayed graft function post transplant
  • able to predict AKI only 24 hour earlier than creatinine

KIDNEY INJURY MODEL-1 (KIM-1) (urine)

  • released from proximal tubule after a variety of injuries
  • can be measured in urine
  • best sensitivity and specificity
  • best at prognosticating early detection of AKI

N-ACETYL-Beta-D-GLUCOSAMINIDASE

  • released from the proximal tubular cells -> into lymph but is not normally filtered
  • appearance in the urine is a pathological sign

OTHER BIOMARKERS

  • L-FABP (liver-type fatty acid binding protein)
  • CD11b
  • IL-6
  • IL-8
  • IL-10
  • matrix metalloproteinase-9
  • glutathione-S-transferase
  • microglobulins
  • retinol binding protein in urine

References and Links

Journal articles

  • Honore PM, Jacobs R, Joannes-Boyau O, Verfaillie L, De Regt J, Van Gorp V, De Waele E, Boer W, Collin V, Spapen HD. Biomarkers for early diagnosis of AKI in the ICU: ready for prime time use at the bedside? Ann Intensive Care. 2012 Jul 2;2(1):24. PMC3475083.
  • Koyner JL. Assessment and diagnosis of renal dysfunction in the ICU. Chest. 2012 Jun;141(6):1584-94. PMC3367482.
  • Moore E, Bellomo R, Nichol A. Biomarkers of acute kidney injury in anesthesia, intensive care and major surgery: from the bench to clinical research to clinical practice. Minerva Anestesiol. 2010 Jun;76(6):425-40. PMID: 20473256.
  • Prowle JR et al. Oliguria as predictive biomarker of acute kidney injury in critically ill patients. Crit Care. 2011 Jul 19;15(4):R172. PMC3387614.

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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