2013 Atherosclerosis--Cystatin C e More than a filtration marker

Invited commentaryCystatin C e More than afiltration marker?Edward R.Smith*Department of Renal Medicine,Eastern Health Clinical School,Faculty of Medicine Nursing&Health Sciences,Monash University,5Arnold Street,Box Hill, Victoria3128,Australiaa r t i c l e i n f oArticle history:Received26June2013Accepted27June2013Available online9July2013Keywords:Cystatin CGFRRisk predictionA reduced glomerularfiltration rate(GFR)is a strong indepen-dent predictor of all-cause and cardiovascular mortality,and is considered by many to confer a cardiovascular risk roughly equiv-alent to that of a previous myocardial infarction[1,2].In routine clinical practice,direct measurement of actual GFR is impractical and is estimated based on the circulating concentration of an endogenous marker,usually creatinine.Since the original obser-vation by Simonsen et al.in1985[3],of a strong inverse correlation between serum cystatin C concentration and GFR,interest in this protein as an alternative to creatinine-based estimates of GFR (eGFR Cr)has grown considerably.Some international guidelines advocate the measurement of serum cystatin C for the confirmation of Chronic Kidney Disease(CKD)in adults with an eGFR Cr of45e 59mL/min/1.73m2,in whom other markers of kidney damage are absent[4].Others have suggested the use of a formula combining serum creatinine and cystatin C concentrations,which may provide a better guide to renal function,particularly in elderly adults with reduced muscle mass[5].Cystatin C is an endogenous inhibitor of matrix-degrading cathepsin cysteine proteases and is important in regulating tissue homeostasis.Ostensibly,cystatin C appears to demonstrate many of the characteristics of an ideal glomerularfiltration marker.It is constitutively expressed and secreted by all nucleated cells and so production is fairly constant,except in certain clinical states[6].It is also minimally protein-bound,and,due to its low molecular weight (13.3kDa)is freelyfiltered by the glomerulus.Finally it is neither secreted by the tubule nor reabsorbed into the systemic circulation [7].However,despite initial optimism that cystatin C might be a more sensitive marker of GFR than creatinine,especially for the detection of mild decrements in renal function[8],there remains no definitive evidence that cystatin C-based estimates of GFR (eGFR CysC)are superior to eGFR Cr as an indicator of measured GFR in the general population[9,10].Yet,compared to eGFR Cr,eGFR CysC has consistently demonstrated a stronger and more linear association with hard outcomes such as all-cause mortality,cardiovascular mortality,and cardiovascular events[11,12].Moreover,in recent analysis of816participants from the Modification of Diet in Renal Disease study(mean age52Æ12years;mean eGFR Cr33Æ11mL/ min/1.73m2),serum cystatin C concentration remained associated with all-cause and cardiovascular mortality,even after adjustment for directly measured GFR using125I-iothalamate[13].In fact, adjustment for measured GFR augmented,rather than attenuated, the strength of the association between cystatin C and outcome (unadjusted HR,1.4095%CI,1.24e1.72;adjusted HR,1.90,95%CI, 1.37e2.63per1SD decrease in1/cystatin C).One potential expla-nation for this somewhat counterintuitivefinding is that cystatin C concentrations may provide a more accurate estimation of inte-grated kidney function than directly measured GFR,which is known to be quite imprecise[14].In other words,it may reflect residual confounding as a result of the imprecision of direct GFR measurement.An alternative,but not exclusive possibility,is that this may reflect the mortality risk associated with non-GFR de-terminants of circulating cystatin C levels.Thus if cystatin C levels are not merely reflecting glomerularfiltration,what are they telling us?In a previous issue of Atherosclerosis,Woitas et al.[15]provide further evidence of this paradox in their report of the association between serum cystatin C and mortality in2998individuals un-dergoing coronary angiography.The study included participants from the Ludwigshafen Risk and Cardiovascular Health(LURIC) cohort(mean age63Æ11years,30%female)and comprised2346 persons with angiography-proven coronary artery disease(CAD) and652controls.Unsurprisingly,in this highly selected cohort, traditional cardiovascular risk factors such as hypertension,dia-betes and a history of previous myocardial infarction were highlyDOI of original article:/10.1016/j.atherosclerosis.2013.04.027. *Tel.:þ61(0)390949557;fax:þ61(0)398996810.E-mail address:ed.smith@.Contents lists available at SciVerse ScienceDirect Atherosclerosisjournal homepa ge:www.elsevie/locate/atherosclerosis0021-9150/$e see front matterÓ2013Elsevier Ireland Ltd.All rights reserved./10.1016/j.atherosclerosis.2013.06.023Atherosclerosis230(2013)73e75。