Question 2

Compare and contrast the utility of the following in the assessment of acute kidney injury in a critically ill patient:

•    Creatinine clearance
•    Serum creatinine
•     Urea
•    Urine output measurements
•    Novel biomarkers

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College Answer

Creatinine Clearance:
•    Gives estimation of Glomerular Filtration Rate (GFR).
•    Requires timed urine collection (usually 24 hours)
•    Accuracy may be limited due to creatinine secretion, thus overestimating
GFR, and incomplete urine collection.
•    Assumes steady state in GFR, which may not be the case in acute renal failure.
•    Determining exact GFR is rarely clinically necessary.

Serum Creatinine:
•    Simple to measure and widely available.
•    Specific for renal function.
•    Indicator of GFR based upon constant production from muscle creatine and relatively constant renal excretion rate.
•    Production may be increased by trauma, fever or immobilisation.
•    Decreased in individuals with small stature cachexia, reduced muscle mass
(eg muscle disease, amputations)
•    Decreased production may occur in liver disease because of decreased hepatic conversion of creatine to creatinine, decreased dietary protein intake, muscle wasting and increased renal tubular secretion of creatinine.
•    May be influenced by volume of distribution changes in critically ill patients

Urea:

•    Simple to measure and widely available
•    Not specific for renal function
•    May be affected by liver disease, protein intake, catabolic state, volume status, upper gastrointestinal bleeding, and drug therapy – eg corticosteroids.

Urine Output:
•    Simple to measure and universally available.
•    More sensitive to changes in renal function than biomarkers
•    Non-specific – can have normal urine output despite severe acute renal failure

Novel Biomarkers:
•    Include a plasma panel (NGAL and cystatin C) and urine panel (NGAL, IL-8 and KIM-1)
•    Represent sequential biomarkers and so have potential for timing the initial insult and assessing the duration of AKI and for predicting overall prognosis
•    May also distinguish between various types and pathogeneses of AKI
•    Potential for high sensitivity and specificity
•    So far only tested in small studies and limited clinical situations and need further validation

Discussion

This question would benefit from a tabulated answer.

A good resource for novel biomarkers is this systematic review in Nature.

A Comparison of Biomarkers in the Assessment of Acute Kidney Injury
Marker	Physiology	Advantages	Disadvantages
Creatinine	A breakdown product of creatine phosphate in muscle Excreted unchanged by the kidneys	Simple to measure Cheap Widely available Indicator of GFR if its production remains constant Indicator of a change in renal function when viewed as a trend	Dependent on muscle metabolism rate remaining normal As renal function worsens, tubular secretion accounts for more of the total creatinine secretion, and its relationship to glomerular filtration rate is thus diluted Relies of accuracy of collection (i.e. did you collect all the urine over 24hrs?) In AKI, frequently overestimates GFR by as much as twofold Increase in creatinine and change in creatinine clearance is delayed for some period after the onset of kidney injury
Creatinine clearance	Correlates with GFR Requires 24hr urine collection Alterantively, can be calculated froms erum creatinine using theCockcroft-Gault formula	Under ideal circumstances, correlates with GFR Cheap Easy to collect Widely available
Urea	Product of ammonia metabolism and thus a product of amino acid deamination. Filtered and excreted passively by the kidney	Simple to measure Cheap Related to pathology (high urea has consequences, eg. encephalopathy and platelet dysfunction)	Less specific than creatinine Elevated in a number of conditions Levels related not only to renal function but also to rates of protein metabolism Influenced by dietary protein intake
Urine output	The fraction of the filtered fluid which is not reabsorbed	Simple to measure Cheap Related to pathology (low urine output can result in fluid overload)	Non-specific, except severely decreased or absent Severe AKI can exist wih normal or increased urine output
Urinary NGAL	neutrophil gelatinase-associated lipocalin a marker of renal tubular inflammation rather than glomerular filtration	performed extremely well in two specific populations: children post cardiac surgery kidney transplant recipients	Less effective in a general ICU population Expensive Experimental Requires urine (there may not be any)
Cystatin C	A 13-kDa, nonglycosylated basic protein, produced at a constant rate by all nucleated cells. Freely filtered by glomeruli and catabolized in tubules	Predicts kidney injury 1-2 days earlier than creatinine	Poor predictor of the need for RRT in a heterogeneous ICU population Expensive Experimental
Urinary IL-8	A marker of renal tubular inflammation -an inflammatory cytokine	Excellent performance in detecting AKI due to ATN	Less helpful in detecting glomerular injury Expensive Experimental
Urinary KIM-1	"Kidney Injury Molecule 1". A urinary protein shed from tubular cells which are undegoing post-ischaemic proliferation.	Highly specific: only shed from tubular cells Highly sensitive: only found in ischaemic ATN, not other forms of renal failure.	Less helpful in detecting glomerular injury Expensive Experimental Only sensitive and specific for one aetiology of AKI

This table is reproduced without any substantial alteration in the Required Reading section on renal injury biomarkers.

References

Parikh, Chirag R., et al. "Urinary interleukin-18 is a marker of human acute tubular necrosis." American Journal of Kidney Diseases 43.3 (2004): 405-414.

Devarajan, Peasad. "Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of kidney disease." Scandinavian Journal of Clinical & Laboratory Investigation 68.S241 (2008): 89-94.

Bennett, Michael, et al. "Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study." CLINICAL JOURNAL-AMERICAN SOCIETY OF NEPHROLOGY 3.3 (2008): 665.

Herget-Rosenthal, Stefan, et al. "Early detection of acute renal failure by serum cystatin C." Kidney international 66.3 (2004): 1115-1122.

Royakkers, Annick ANM, et al. "Serum and urine cystatin C are poor biomarkers for acute kidney injury and renal replacement therapy." Intensive care medicine 37.3 (2011): 493-501.

Coca, S. G., et al. "Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review." Kidney international 73.9 (2007): 1008-1016.

Shemesh, Ovadia, et al. "Limitations of creatinine as a filtration marker in glomerulopathic patients." Kidney Int 28.5 (1985): 830-838.

Waikar, Sushrut S., and Joseph V. Bonventre. "Creatinine kinetics and the definition of acute kidney injury." Journal of the American Society of Nephrology20.3 (2009): 672-679.

Bellomo, Rinaldo, et al. "Acute renal failure–definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group." Critical care 8.4 (2004): R204.

Cockcroft, Donald W., and M. Henry Gault. "Prediction of creatinine clearance from serum creatinine." Nephron 16.1 (1976): 31-41.

Han, Won K., et al. "Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury." Kidney international 62.1 (2002): 237-244.

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