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Introduction

Kidney disease is associated with substantial morbidity and mortality, emphasising the importance of diagnosis and monitoring. Establishing the presence of kidney disease can be difficult, due to the many aetiologies, and the assays ability to identify the disease at the earliest possible occurrence. The cause may be pre-renal, as seen with hypovolaemia; intrinsic renal disease, such as diabetic. nephropathy, and post-renal, due to an obstruction, such as benign prostatic hyperplasia. To this end, many different biochemical markers exist, predominately in blood and urine, which can be used as markers of renal function or renal injury. Other markers may also be measured in kidney disease in order to assess the effect of kidney function on pathophysiological processes.

Some markers of renal function are used to determine glomerular filtration rate (GFR). Despite the kidney performing a wide array of functions, GFR is considered to be a robust indicator of renal function (1). It is defined. as the volume of plasma that can be cleared of a particular analyte per unit time. The ideal marker of GFR is a

substance that is endogenously produced by the body at a relatively fixed rate, freely filtered at the glomerulus, without being secreted or reabsorbed by the tubules, and does not undergo extrarenal elimination (2). For example, urea is seen as a poor marker of GFR, as it is produced at variable rates, undergoes marked reabsorption by the tubules, and its level is influenced by many other conditions, such as liver disease (3).

The kidneys are responsible for many roles essential to life, such as filtering the blood of metabolic wastes and toxins, endocrine functions, and maintaining the composition of the extracellular fluid (ECF). Assessing these functions individually can be difficult and expensive, so a versatile marker of kidney function is desirable. Creatinine is used to stage chronic kidney disease (CKD), along with urine albumin content if the abnormalities have persisted for longer than 3 months (4), and acute kidney injury (AKI) (5). Exogenous substances, such as inulin and radioisotopic markers, provide the most accurate estimation of GFR (6,7), but have a number of disadvantages, they are time Table 1 Creatinine interferences using the Jaffe method

Creatinine interferences

Substances causing positive creatinine interference in the

Jaffe reaction

Ascorbic acid (10)

Pyruvate (10)

Protein (10)

Glucose (10)

Creatine (10)

Various cephalosporins (10)

Acetoacetate (11)

Fluorescein (12)

Substances causing negative creatinine interference in the

Jaffe reaction

Dopamine/L-DOPA/methyldopa (13)

Bilirubin (10)

Haemoglobin F (10)

consuming procedures, not routinely available, and possible. radiation exposure (8). An endogenous marker that can circumvent these limitations is desirable.

Plasma biomarkers of renal function

These are markers that can be measured in a plasma (or serum) sample in order to give a numeric value that either directly indicates renal function, or can be inserted into a formula that estimates a parameter related to renal function, such as estimated GFR (eGFR).

Creatinine

Creatinine is the most widely available and commonly used. biomarker of renal function. It is derived from creatine, which is used in muscles as a quick-acting store of energy. Creatine undergoes spontaneous, irreversible conversion to its anhydride form, creatinine. While creatinine is freely filtered and minimally reabsorbed, 20-30% is also secreted by the proximal tubule (9), thus overestimating the creatinine and underestimating the eGFR, but this is somewhat offset in the Jaffe method by the non-creatinine chromogens (Table 1). In addition to these multiple methodological interferents, a further limitation of using creatinine to determine GFR is evidenced by the curvilinear relationship between creatinine and GFR, which makes it prone to not being able to detect mild to moderate reductions in GFR clearly (1) if the reference interval of creatinine is 50-100 pmol/L., and a patient has an initial result of 50 µmol/L. and follow-up result of 100 µmol/L., there GFR will have halved, despite their creatinine being within the emphasises two key points rega should be used where possible to GI

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formula section), and comparing a p...

to thei

previous values is more important than comparing a patient's values to a reference interval.

The most widely used method to determine creatinine level is the Jaffe reaction and its variations (14), based on the detection of colour change when creatinine reacts with alkaline picrate. Whilst it is relatively inexpensive and the most widely used, it is liable to a number of common interferents, such as ketones (positive interferent) and bilirubin (negative interferent) (15), refer to Table 1. Furthermore, these interferents are often very difficult to remove without compromising the specimen. Analysing platforms used in the laboratory ose aqueous calibrators that do not have consistent levels of these interfering chromogens in them, creating biases between laboratories and instruments of up to 20% (16). Other methods used to determine creatinine

concentration include the various enzymatic methods, and chromatographic methods. Enzymatic methods, typically used in point of care testing, are routinely more expensive, despite being less associated with interferents (although not immune) than the Jaffe method (17). They typically use hydrogen peroxide in their reactions, so may be liable to interference from an antioxidant, such as vitamin C. Chromatographic methods are more accurate than the Jaffe methods, but are not widely available, have a long turnaround time, and require specialised instrumentation and labour. The differences between methods and between calibrators, and patient samples (non-commutability) limits the transference of results between laboratories.

Cystatin C

Cystatin C is a marker of renal function that offers potential advantages over creatinine. It is a small protein (approximately 13 kDa) produced by all nucleated cells, so is less dependent on muscle mass, although it may be increased in hyperthyroidism, corticosteroid use, and rapid cell turnover (18,19). Cystatin C is typically measured