Closer to the ideal

Xchange newsletter, issue 25 – Summer 2008

Chronic kidney disease (CKD) is slow permanent loss of kidney function over months to years. Patients with advanced CKD have a risk of co-morbidity and mortality. Recognised as a major public health concern, Quality Management and Analysis System (QMAS) data published on 28 September 2007 shows an overall adult prevalence of CKD of 3%.

Cystatin C (CysC) screening may be used as an alternative to creatinine and creatinine clearance to screen for and monitor kidney dysfunction in patients with suspected kidney disease and has been suggested to be closer to the ‘ideal’ CKD marker [1]. A turbidimetric Cystatin C assay for Abbott’s ARCHITECT clinical chemistry systems is under development.

Measuring kidney dysfunction

CysC is a low molecular weight protein that is produced by all nucleated cells. It is created at a constant rate and is found in body fluids such as serum, spinal fluid and breast milk. CysC, with other substances such as creatinine and glucose, is freely filtered out of the blood by the kidney’s glomerular blood vessels and catabolised when reabsorbed.

Glomerular Filtration Rate (GFR) is the volume of plasma that can be completely cleared of a particular substance by the kidneys in a unit of time. Kidney dysfunction will result in low GFR which can be measured by screening for increased levels of filtrands.

Endogenous serum markers

While it is currently common to screen for elevated concentrations of endogenous serum markers such as urea and creatinine, these markers do not perform optimally in certain clinical settings [2].

A large portion of urea (40-70%) is passively absorbed through the renal tubules, so in situations of decreased renal perfusion some filtered urea will return to the bloodstream causing underestimates of GFR. Additionally, concentrations in the blood can vary with diet, hepatic function and numerous disease states [2].

Early kidney impairment may not cause elevated creatinine levels or symptoms. Creatinine and urea levels remain in the normal range until approximately half of the kidney function is lost.

Additionally, as creatinine is produced in the muscles, screening is problematic in patients with liver cirrhosis, obesity, malnourishment or very small muscle mass. Results are also affected by age and gender and, depending on the measurement technique, can be subject to analytic interferences from substances such as glucose, uric acid, ketones, plasma proteins and cephalosporins [2].

Calculation of creatinine clearance (CrCl) by determining concentration levels in timed urine collections and simultaneously in blood is a cumbersome method, prone to error in the outpatient setting. Numerous formulae and nomograms have been developed for estimating creatinine clearance from the serum creatinine concentration, thereby bypassing the need for urine collection. However, as these formulae assume stability of renal function and are based on the principle that creatinine excretion is constant and equal to creatinine production, which, in turn, is proportional to muscle mass, results will be meaningless in situations where the serum creatinine concentration is rising or falling [3]. 

Solving problem situations

CysC is not secreted, but is reabsorbed by tubular epithelial cells and subsequently catabolised so that it does not return to the blood flow. It is produced throughout the body at a constant rate and should remain at a steady state in the blood if the kidneys are working efficiently and GFR is normal. The use of serum CysC to estimate GFR is based on the same logic as the use of other endogenous markers but, because it does not return to the bloodstream and is not secreted by renal tubules, it has unique advantages over traditional markers.

Studies suggest that CysC may be a more sensitive marker of renal damage especially when the problems of creatinine are most apparent and early detection of decreased GFR may be important to identify people developing Chronic Kidney Disease. These cases include children, adults over 75, pregnant women, patients with diabetes and settings prone to acute, initially minor, renal damage, such as renal transplant, chemotherapy, cirrhosis and autoimmune disease [2].

References

[1] Grubb, A.O., Adv Clin Chem 35: 63-99 (2000)
[2] Laterza O, et al, Clin Chem 48:5 699-707 (2002)
[3] Perrone, R.D., et al, Clin Chem 38: 1933-53 (1992)
[4] DoH National Service Framework for Renal Services - Part Two