CYSTATIN C ASSAY - cont'd

Kidney function

GFR is best measured by injecting compounds such as inulin, radioisotopes such as 51chromium-EDTA, 125I-iothalamate, 99mTc-DTPA or radiocontrast agents such as iohexol, but these techniques are complicated, costly, time-consuming and have potential side-effects. Creatinine is the most widely used biomarker of kidney function. It is inaccurate at detecting mild renal impairment, and levels can vary with muscle mass and protein intake. Formulas such as the Cockcroft and Gault formula and the MDRD formula try to adjust for these variables.
Cystatin C has a low molecular weight (approximately 13.3 kilodaltons), and it is removed from the bloodstream by glomerular filtration in the kidneys. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. Serum levels of cystatin C are a more precise test of kidney function (as represented by the glomerular filtration rate, GFR) than serum creatinine levels. This finding is based mainly on cross-sectional studies (on a single point in time). Longitudinal studies (that follow cystatin C over time) are scarcer; some studies show promising results. Cystatin C levels are less dependent on age, sex, race and muscle mass compared to creatinine. Cystatin C measurements alone have not been shown to be superior to formula-adjusted estimations of kidney function. As opposed to previous claims, cystatin C has been found to be influenced by body composition. It has been suggested that cystatin C might predict the risk of developing chronic kidney disease, thereby signaling a state of 'preclinical' kidney dysfunction.
Studies have also investigated cystatin C as a marker of kidney function in the adjustment of medication dosages.
Cystatin C levels have been reported to be altered in patients with cancer, (even subtle) thyroid dysfunction and glucocorticoid therapy in some but not all[ situations. Other reports have found that levels are influenced by cigarette smoking and levels of C-reactive protein. Levels seem to be increased in HIV infection, which might or might not reflect actual renal dysfunction. The role of cystatin C to monitor GFR during pregnancy remains controversial. Like creatinine, the elimination of cystatin C via routes other than the kidney increase with worsening GFR.


cardiovascular disease

Kidney dysfunction increases the risk of death and cardiovascular disease. Several studies have found that increased levels of cystatin C are associated with the risk of death, several types of cardiovascular disease (including myocardial infarction, stroke, heart failure, peripheral arterial disease and metabolic syndrome) and healthy aging. Some studies have found cystatin C to be better in this regard than serum creatinine or creatinine-based GFR equations. Because the association of cystatin C with long term outcomes has appeared stronger than what could be expected for GFR, it has been hypothesized that cystatin C might also be linked to mortality in a way independent of kidney function. In keeping with its housekeeping gene properties, it has been suggested that cystatin C might be influenced by the basal metabolic rate.


Neurological disorders

Mutations in the cystatin 3 gene are responsible for the Icelandic type of hereditary cerebral amyloid angiopathy, a condition predisposing to intracerebral haemorrhage, stroke and dementia. The condition is inherited in a dominant fashion.
Since cystatin 3 also binds amyloid β and reduces its aggregation and deposition, it is a potential target in Alzheimer's disease. Although not all studies have confirmed this, the overall evidence is in favor of are role for CST3 as a susceptibility gene for Alzheimer's disease. Cystatin C levels have been reported to be higher in subjects with Alzheimer's disease.
The role of cystatin C in multiple sclerosis and other demyelinating diseases (characterized by a loss of the myelin nerve sheath) remains controversial.


OTHER ROLES

Cystatin C levels are decreased in atherosclerotic (so-called 'hardening' of the arteries) and aneurysmal (saccular bulging) lesions of the aorta. Genetic and prognostic studies also suggest a role for cystatin C. Breakdown of parts of the vessel wall in these conditions is thought to result from an imbalance between proteinases (cysteine proteases and matrix metalloproteinases, increased) and their inhibitors (such as cystatin C, decreased).
A few studies have looked at the role of cystatin C or the CST3 gene in age-related macular degeneration. Cystatin C has also been investigated as a prognostic marker in several forms of cancer. Its role in pre-eclampsia remains to be confirmed.