cystatin c - more than a filtration marker_

Invited commentary

Cystatin C e More than a ?ltration marker?

Edward R.Smith *

Department of Renal Medicine,Eastern Health Clinical School,Faculty of Medicine Nursing &Health Sciences,Monash University,5Arnold Street,Box Hill,Victoria 3128,Australia

a r t i c l e i n f o

Article history:

Received 26June 2013Accepted 27June 2013

Available online 9July 2013Keywords:Cystatin C GFR

Risk prediction

A reduced glomerular ?ltration 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.in 1985[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 con ?rmation of Chronic Kidney Disease (CKD)in adults with an eGFR Cr of 45e 59mL/min/1.73m 2,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 glomerular ?ltration 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 freely ?ltered 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 de ?nitive 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 of 816participants from the Modi ?cation of Diet in Renal Disease study (mean age 52?12years;mean eGFR Cr 33?11mL/min/1.73m 2),serum cystatin C concentration remained associated with all-cause and cardiovascular mortality,even after adjustment for directly measured GFR using 125I-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,1.24e 1.72;adjusted HR,1.90,95%CI,1.37e 2.63per 1SD decrease in 1/cystatin C).One potential expla-nation for this somewhat counterintuitive ?nding 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 re ?ect residual confounding as a result of the imprecision of direct GFR measurement.An alternative,but not exclusive possibility,is that this may re ?ect the mortality risk associated with non-GFR de-terminants of circulating cystatin C levels.Thus if cystatin C levels are not merely re ?ecting glomerular ?ltration,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 in 2998individuals un-dergoing coronary angiography.The study included participants from the Ludwigshafen Risk and Cardiovascular Health (LURIC)cohort (mean age 63?11years,30%female)and comprised 2346persons with angiography-proven coronary artery disease (CAD)and 652controls.Unsurprisingly,in this highly selected cohort,traditional cardiovascular risk factors such as hypertension,dia-betes and a history of previous myocardial infarction were highly

DOI of original article:https://www.360docs.net/doc/8f451394.html,/10.1016/j.atherosclerosis.2013.04.027.*Tel.:t61(0)390949557;fax:t61(0)398996810.E-mail address:ed.smith@https://www.360docs.net/doc/8f451394.html,

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Atherosclerosis 230(2013)73e

prevalent.The mean eGFR Cr (based on the Chronic Kidney Disease Epidemiology Collaboration formula)was 83?23mL/min/1.73m 2in those with CAD and was marginally higher in those without CAD (mean 89?18mL/min/1.73m 2;P ?0.047).Participants were fol-lowed for a median 9.9years during which time 898deaths occurred,555due to cardiovascular disease (CVD)and the remaining 326due to other causes.After hierarchical adjustment for potential confounders,ascending quartiles of cystatin C con-centration were found to be independently predictive of both all-cause and CV mortality,with those individuals in the highest quartile of cystatin C concentrations at approximately twice the risk of death compared to those in the reference quartile.Furthermore,on a linear scale,a one standard deviation increase in log-transformed cystatin C concentration was associated with a mean 31and 36%increased risk of all-cause and cardiovascular death,respectively.As might be expected,hazard ratios were signi ?cantly,but not completely,attenuated by addition of eGFR Cr and CV risk factors (including CAD).The greatest relative attenuation,however,was seen with adjustment for age,gender and BMI.Consistent with previous reports [16e 18],some degree of confounding by age and BMI was expected given that ascending quartiles of cystatin C were signi ?cantly associated with these variables in baseline cross-sectional analysis.Unfortunately,the authors did not consider the effects of age and BMI separately.Other studies have related cys-tatin C concentration to adiposity [17,19],thus it would seem likely that fat mass or fat composition is not only an important determi-nant of circulating concentrations (cystatin C expression is appar-ently much higher in adipose stromal cells from obese compared to non-obese subjects [20]),but that adipose-related risk factors may at least in part account for association with outcome.Indeed,in the present study,cystatin C levels were also associated with

hyper-tension,higher C-reactive protein and lower HDL-cholesterol con-centrations,which together with higher BMI represent a constellation factors that are often associated with insulin resis-tance.This recapitulates an earlier observation by Servais et al.,that cystatin C may have some as yet unde ?ned role in the metabolic syndrome [21].Importantly,BMI is a poor surrogate of adiposity and further investigations are needed to evaluate whether more accu-rate measures of fat mass impact on the observed relationship.Moreover,adiposity-associated determinants of cystatin C may not be independent of GFR and renal function.Increased adiposity is associated with changes in renal haemodynamics,glomerular pa-thology and proteinuria [22,23].Taken together with the fact that deposition of fat within the kidney is also associated with increased risk of renal impairment [22],increased adiposity is regarded by many,as a bone ?de risk factor for CKD.

It is perhaps noteworthy that despite the initial assertion by Woitas et al.,[15]that this is a cohort “without overt renal insuf-?ciency ”,it is clear that some individuals in the highest quartile may have had some degree of renal impairment (mean eGFR Cr 66?21mL/min/1.73m 2).Although the authors ’con ?rmed their ?ndings after excluding 367participants with an eGFR Cr <60mL/min/1.73m 2or serum creatinine concentration >2mg/dL (177m mol/L),thus moderating the possibility of confounding related to the presence of kidney disease,the lack of adjustment for some measure of proteinuria represents a signi ?cant,but acknowledged,shortcoming.Thus,with respect to this study,we cannot be certain that cystatin C is associated with outcome,in-dependent of “true ”GFR or some other aspect of renal pathology not re ?ected in the measurement of eGFR Cr .

Regardless of these mechanistic considerations,it seems clear that cystatin C concentration captures some additional aspect of risk of death to eGFR Cr .Again,consistent with other recent reports of cohorts more representative of the general population [24e 26],Woitas et al.also show that addition of cystatin C concentration to a

model containing a battery of established CV risk factors enhanced discriminative and reclassi ?cation performance metrics [15].Although addition of cystatin C only yielded a small non-signi ?cant increment in c -statistic,which is to be expected given the high initial value for the AUC and the relative insensitivity of the method to the addition of a single marker,both net reclassi ?cation and integrated discrimination indices increased signi ?cantly (30%and 4%respectively,for CV mortality).Regrettably,whether the improvement in reclassi ?cation speci ?cally applied to those sub-jects who did or did not reach outcome was not reported.Other studies suggest that improvement is mainly observed in those in-dividuals who reach outcome (i.e.an upward reclassi ?cation of risk in those who subsequently died)with little effect on non-event reclassi ?cation [24].

Overall,the study by Woitas et al.[15]provides persuasive and con ?rmatory evidence of the added value of cystatin C ascertain-ment,at least for purposes of prognostication.It is also clear that cystatin C concentration is not solely dependent on GFR,and consideration of these factors,particularly central adiposity,should be made when attempting to interpret results.While it is conceivable that residual confounding with renal function may,to some degree,account for the consistent association between cys-tatin C and mortality independent of eGFR cr (or even measured GFR),it is unlikely to fully explain the strong association with outcomes,particularly in cohorts such as this,where renal function is well preserved.Although this key issue remains unresolved,given that cystatin C appears to so faithfully re ?ect outcome,it is debatable whether such uncertainty in its meaning necessarily detracts from its potential clinical utility.Further work is needed to de ?ne and validate the incorporation of cystatin C into clinical beyond con ?rmatory testing for CKD.Con ?icts of interest

ERS has received research funding from Amgen and Baxter and honoraria from Shire.Acknowledgements

Thanks to Prof.Stephen G.Holt for critical reading and suggestions.References

[1]van der Velde M,Matsushita K,Coresh J,Astor BC,Woodward M,Levey A,

et al.Lower estimated glomerular ?ltration rate and higher albuminuria are associated with all-cause and cardiovascular mortality.A collaborative meta-analysis of high-risk population cohorts.Kidney Int 2011;79:1341e 52.

[2]Tonelli M,Muntner P,Lloyd A,Manns BJ,Klarenbach S,Pannu N,et al.Risk of

coronary events in people with chronic kidney disease compared with those with diabetes:a population-level cohort https://www.360docs.net/doc/8f451394.html,ncet 2012;380:807e 14.[3]Simonsen O,Grubb A,Thysell H.The blood serum concentration of cystatin C

(gamma-trace)as a measure of the glomerular ?ltration rate.Scand J Clin Lab Invest 1985;45:97e 101.

[4]Kidney Disese:Improving Global Outcomes (KDIGO)CKD Work Group.KDIGO

clinical practice guideline for the evaluation and management of chronic kidney disease.chapter 1:de ?nition and classi ?cation of CKD.Kidney Int Suppl 2013;3:19e 62.

[5]Inker LA,Schmid CH,Tighiouart H,Eckfeldt JH,Feldman HI,Greene T,et al.

Estimating glomerular ?ltration rate from serum creatinine and cystatin C.N Engl J Med 2012;367:20e 9.

[6]Knight EL,Verhave JC,Spiegelman D,Hillege HL,de Zeeuw D,Curhan GC,et al.

Factors in ?uencing serum cystatin C levels other than renal function and the impact on renal function measurement.Kidney Int 2004;65:1416e 21.

[7]Tenstad O,Roald AB,Grubb A,Aukland K.Renal handling of radiolabelled

human cystatin C in the rat.Scand J Clin Lab Invest 1996;56:409e 14.

[8]Dharnidharka VR,Kwon C,Stevens G.Serum cystatin C is superior to serum

creatinine as a marker of kidney function:a meta-analysis.Am J Kidney Dis 2002;40:221e 6.

[9]Inker LA,Okparavero A.Cystatin C as a marker of glomerular ?ltration rate:

prospects and limitations.Curr Opin Nephrol Hypertens 2011;20:631e 9.

E.R.Smith /Atherosclerosis 230(2013)73e 75

[10]Rule AD,Bailey KR,Lieske JC,Peyser PA,Turner ST.Estimating the glomerular

?ltration rate from serum creatinine is better than from cystatin C for eval-uating risk factors associated with chronic kidney disease.Kidney Int 2013;83:1169e76.

[11]Ix JH,Shlipak MG,Chertow GM,Whooley MA.Association of cystatin C with

mortality,cardiovascular events,and incident heart failure among persons with coronary heart disease:data from the Heart and Soul Study.Circulation 2007;115:173e9.

[12]Shlipak MG,Katz R,Sarnak MJ,Fried LF,Newman AB,Stehman-Breen C,

et al.Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease.Ann Intern Med2006;145: 237e46.

[13]Tangri N,Inker LA,Tighiouart H,Sorensen E,Menon V,Beck G,et al.Filtration

markers may have prognostic value independent of glomerular?ltration rate.

J Am Soc Nephrol2012;23:351e9.

[14]Kwong YT,Stevens LA,Selvin E,Zhang YL,Greene T,Van Lente F,et al.

Imprecision of urinary iothalamate clearance as a gold-standard measure of GFR decreases the diagnostic accuracy of kidney function estimating equa-tions.Am J Kidney Dis2010;56:39e49.

[15]Woitas RP,Kleber ME,Meinitzer A,Grammer TB,Silbernagel G,Pilz S,et al.

Cystatin C is independently associated with total and cardiovascular mortality in individuals undergoing coronary angiography.The Ludwigshafen Risk and Cardiovascular Health(LURIC)study.Atherosclerosis2013;229(2):541e8. [16]Parikh NI,Hwang SJ,Yang Q,Larson MG,Guo CY,Robins SJ,et al.Clinical

correlates and heritability of cystatin C(from the Framingham Offspring Study).Am J Cardiol2008;102:1194e8.

[17]Chew-Harris JS,Florkowski CM,George PM,Elmslie JL,Endre ZH.The relative

effects of fat versus muscle mass on cystatin C and estimates of renal function in healthy young men.Ann Clin Biochem2013;50:39e46.[18]Shankar A,Teppala S.Relationship between body mass index and high cys-

tatin levels among US adults.J Clin Hypertens(Greenwich)2011;13:925e30.

[19]Macdonald J,Marcora S,Jibani M,Roberts G,Kumwenda M,Glover R,et al.

GFR estimation using cystatin C is not independent of body composition.Am J Kidney Dis2006;48:712e9.

[20]Naour N,Fellahi S,Renucci JF,Poitou C,Rouault C,Basdevant A,et al.Potential

contribution of adipose tissue to elevated serum cystatin C in human obesity.

Obes(Silver Spring)2009;17:2121e6.

[21]Servais A,Giral P,Bernard M,Bruckert E,Deray G,Isnard Bagnis C.Is serum

cystatin-C a reliable marker for metabolic syndrome?Am J Med2008;121: 426e32.

[22]Serra A,Romero R,Lopez D,Navarro M,Esteve A,Perez N,et al.Renal injury in

the extremely obese patients with normal renal function.Kidney Int2008;73: 947e55.

[23]Foster MC,Hwang SJ,Porter SA,Massaro JM,Hoffmann U,Fox CS.Fatty kid-

ney,hypertension,and chronic kidney disease:the framingham heart study.

Hypertension2011;58:784e90.

[24]Foster MC,Inker LA,Levey AS,Selvin E,Eckfeldt J,Juraschek SP,et al.Novel

?ltration markers as predictors of all-cause and cardiovascular mortality in US adults.Am J Kidney Dis2013;62:42e51.

[25]Waheed S,Matsushita K,Sang Y,Hoogeveen R,Ballantyne C,Coresh J,et al.

Combined association of albuminuria and cystatin C-based estimated GFR with mortality,coronary heart disease,and heart failure outcomes:the Atherosclerosis Risk in Communities(ARIC)Study.Am J Kidney Dis2012;60: 207e16.

[26]Astor BC,Sha?T,Hoogeveen RC,Matsushita K,Ballantyne CM,Inker LA,

et al.Novel markers of kidney function as predictors of ESRD,cardiovas-cular disease,and mortality in the general population.Am J Kidney Dis 2012;59:653e62.

E.R.Smith/Atherosclerosis230(2013)73e7575