Blog entry by Meguid El Nahas
Cystatin C and creatinine as markers of bleeding complications, cardiovascular events and mortality during oral anticoagulant treatment. Marcus Lind a,⁎, Jan-Håkan Jansson a, Torbjörn K. Nilsson b, Lisbeth Slunga Järvholm a, Lars Johansson a
a Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden b Department of Clinical Chemistry, Örebro University Hospital, Örebro, Sweden Introduction: Impaired kidney function has been linked to both ischemic events as well as bleeding complica- tions in several clinical conditions. Our aim was to investigate if cystatin C, creatinine and calculated glomerular filtration rate (eGFR) were related to future risk of bleeding complications, cardiovascular events or all-cause mortality during oral anticoagulant treatment.
Materials and methods: In a cohort study, 719 patients on long-term vitamin K antagonist (VKA) treatment were followed for a mean of 4.2 years. Blood sampling was taken at inclusion and patients were followed prospectively. Cystatin C and creatinine were analysed and eGFR was calculated. All medical records were reviewed. Major bleeding events, myocardial infarctions, strokes, arterial emboli, and deaths were recorded and classified. Results: After adjustment for age, no association between cystatin C, creatinine or eGFR and major bleeding was found. Cystatin C was independently associated with cardiovascular events (hazard ratio 1.50 (95% CI: 1.27-1.77)) and all-cause mortality (hazard ratio 1.62 (95% CI: 1.38-1.90)).Creatinine was only associated with all-cause mortality, while eGFR was not associated with any of the outcomes.
Conclusions: Our findings underscore the superiority of cystatin C as a marker of cardiovascular risk compared to creatinine or eGFR. VKA-treated patients with increased cystatin C levels should be considered to be at an increased risk of cardiovascular events, and not bleeding complications.
Predictors of all cause CVD and mortality in a selected population showing that:
Serum Cystatin C predicts CVD events as well as all cause mortality.
Serum Creatinine predicts all cause mortality only.
eGFR: doesnt predict anything!
This observation made in a selected group of individuals on anticoagulation agrees with more general observations made in the general population by Astor et al last year (2012) that Cystatin C was superior to Cr-based eGFR in predicting outcomes; Heart failure, CAD, Mortality and even ESRD. http://www.ncbi.nlm.nih.gov/pubmed/22305758
The explanation is probably multifactorial including the fact that it is most likely that it is the non-renal aspects of either serum creatinine (wasting, sarcopenia, and catabolism) or Cystatin C (inflammation, obesity, smoking) that drive the association between low calculated eGFR and outcomes previously reported by a number of large community-based studies. http://www.ncbi.nlm.nih.gov/pubmed/21307840
Of interest in the Astor study, other filtration markers that have inflammatory associations such Beta2-microglobulin (b2M) and Beta Trace Protein (BTP) showed a superiority to serum creatinine and derived equations in predciting cardiovascular and mortality outcomes.
Overall, the inclusion of CystatinC and CysC related eGFR equations improves considerably the mortality risk prediction compared to Cr-based eGFR derivations and CKD classification. This was recently highlighted by the article of Shlipak et al (NEJM September 2013), although these authors remain unable to appreciate that it is serum Cystain C level that matters and not the eGFR derivation... http://www.nejm.org/doi/pdf/10.1056/NEJMoa1214234
So the question has to be asked, whether it is a low eGFR that predicts CV and all cause mortality as repeatdly and stubornly stated or whether it is the components that make up the eGFR calculation: sCreatinine and sCystatin C that truly determine outcomes?
And does it matter?
The answer is yes, it does matter as we have been indoctrinated over the last 5-10 years with the concept that low eGFR is worth detecting and justify population screening because...it predicts cardiovascular as well as all cause mortality. Further, such an assumption has been the basis of the new (2013) KDIGO CKD classification and its risk stratification.
Well, if all it takes is to go back to the good old serum creatinine (or urine creatinine for that matter) and rediscover that individuals in the lower quartiles of the serum creatinine range for their age are at increased risk of CV and all cause mortality, then we start wandering about the whole foundation of the eGFR based stratification of individuals. Low serum creatinine is a poor prognostic predictor based on wasting and sarcopenia, whilst a high serum creatinine tells us all we need to know about renal function and its progression...and for good measure we would also measure CystatinC in those we clinically deem to be at high CVD morbidity and mortality. Other biomarkers that are equally useful would be the good old C-Reactive protein. http://www.ncbi.nlm.nih.gov/pubmed/23975559
A step back to the future would take us back in the future to simple and reliable predictors of outcomes (renal and mortality) and away from a complicated eGFR based classification system. It would have the added advantage of avoidance of medicalisation of older "normal" individuals based on a creatinine based formulation that appears to be wanting in its primary function, that of predicting renal and cardiovascular outcomes....