Alliance 5 using collaborative enquiry as an approach to professional development

Cystatin C is a non-glycosylated low molecular weight protein with molecular mass of 12.8KDa having 122 amino acid and belongs to the family of cysteine protease inhibitor

22. It is synthesized by all nucleated cells at a constant rate^22,67. It is freely filtered at the glomerulus than other low molecular weight proteins such as β2 microglobulin and retinol binding protein(RBP) due to its small size and high isoelectric point (pI 9.2)². Approximately 99% of filtered cystatin C is reabsorbed and completely degraded at the tubular level particularly proximal tubule with the remaining un-catabolized form eliminated in the urine without being reabsorbed into the plasma and without undergoing tubular secretion^1,68. However, there is an evidence suggesting tubular secretion of cystatin C in hypertensive patients although an assay imprecision could be a reason^69-70. In addition, some studies have suggested influence of thyroid hormones

71-73.

Plasma concentration of cystatin C appears unaffected by muscle mass, diet, race or gender. This is supported by a study done in Lagos where 59 children were assessed

31 for cystatin C and creatinine, it was observed that there was no correlation between cystatin C and weight, age, height or BMI after 2years ⁷⁴.

In a study on Cystatin C in hypertensive non diabetic patients with CKD pre-dialysis, it was observed that Cystatin C is not affected by extra-renal parameters and at the level of CKD serum cystatin C correlated well with creatinine⁷⁵. Unlike serum creatinine, there are no known extra-renal routes of elimination of cystatin C⁶⁸. Its clearance from the circulation is only by glomerular filtration^76-77. Cystatin C measurement appears to be unaffected by spectral interferences affecting creatinine assays⁷⁸.

There are a number of studies documenting correlation between Creatinine and Cystatin C (as reciprocal) and GFR as assessed by ⁵⁵Cr-EDTA clearance or using a number of alternative exogenous markers. The correlations vary between 0.32 and 0.88 for cystatin C and 0.25 and 0.89 in case of creatinine. In almost all cases the correlation with cystatin C is superior to that of creatinine⁷⁹. This was first demonstrated using receiver operator curve to analyze the superiority of cystatin C measurement compared to creatinine for the detection of kidney disease. This has been confirmed by a 2002 metaanalysis^80-81. A 2002 summary receiver operator curve analysis of all the studies at the time of publication showed an area under the curve of 0.95 for cystatin c and 0.91 for creatinine (p=0.003)⁸². Two other meta-analysis also concluded that serum cystatin

32 C is superior to serum creatinine as a marker of kidney disease. However, formula based GFR using combination of creatinine and cystatin C has been suggested^{5, 83-84}. Perhaps more critically, another study found that in a group of patients with a range of GFRs, the cystatin C concentration increased sooner than creatinine as GFR declined²². Cystatin C concentration started to increase as GFR fell below 80ml/min/1.73m² compared with about 40ml/min/1.73m² for serum creatinine^{76, 81}. It was also concluded that cystatin C-GFR was better than creatinine-GFR at levels >

60ml/min/1.73m².⁸⁵ In a study among diabetic patients, it was observed that cystatin C-GFR appears to be better correlated with microalbuminuria while MDRD and Cockroft-Gault creatinine estimates of GFR tend to reflect only proteinuria⁸⁶. Cystatin C is therefore very useful when trying to detect early stages of CKD^77,87.

The sensitivity of serum Cystatin C has been thought to be superior to that of Creatinine in a study investigating the relationship between serum Cystatin C and Creatinine in kidney and liver transplant patients. It was concluded that serum Cystatin C was a better marker of GFR than the widely used Creatinine in liver and renal transplant patients⁸⁸. Another study compared Cystatin C, creatinine and Cockroft-Gault formula for eGFR with ¹²⁵I method in 123 patients with type 2 DM and found a good correlation between Cystatin C and GFR⁸⁹. It was concluded that in addition to Cystatin C being a superior marker of eGFR, it is a more sensitive marker of small changes in GFR.^22,76

33 Conversely, it was reported that Cystatin C levels significantly correlated with creatinine and creatinine clearance in assessing renal function in patients with neoplasms of the muscle⁹⁰. Similarly, a correlation study of serum Creatinine and Cystatin C with a reference method using 19 pediatric patients, it was observed that there was no significant difference between serum Cystatin C and Creatinine for monitoring post renal transplant⁹¹. However, a systemic review that compared the diagnostic accuracy of Cystatin C with serum Creatinine reported that Cystatin C is a reliable marker of GFR^92.

This is particularly important in patients with mild to moderate impaired kidney function.

Cystatin C also had a higher chance of detecting true renal impairment when compared with serum creatinine^92-93. This high degree of sensitivity has been demonstrated in both type 1 and type 2 diabetic patients⁹⁴. This is supported by a report that Cystatin C has a better discriminatory capabilities than Iohexol clearance in the GFR range of 10 to 20ml/min/1.73m² corresponding to Cystatin C values of 2.5 to 4.4mg/L⁹⁵.

Twenty nine studies including 21 in adults reported before 2009 compared serum creatinine with Cystatin C in CKD patients. Seventeen (17) studies showed that Cystatin C was a better predictor of GFR while 12 showed no difference in the prediction of GFR⁹⁶. A study comparing a Cystatin C formula to Ceatinine based formulas showed cytatin C was more likely to correctly predict that the patients GFR was below or above 60ml/min/1.73m² than the MDRD formula using creatinine⁹³. Elevated cystatin C has

34 recently been identified as a significant prognostic indicator for the development of cardiovascular disease in people with diabetes especially the elderly⁹⁷ and in general population with no known CKD⁹⁸.

35 CHAPTER THREE