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.