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....
Primary FSGS is a clinicopathologic entity characterized by sclerotic changes affecting only a portion (segmental) of some glomeruli (focal). Symptoms related to this glomerular lesion include isolated proteinuria or steroid-resistant nephrotic syndrome (SRNS) .
The clinical phenotypes of FSGS are either nonsyndromic FSGS where the disease is limited to the kidney; or syndromic FSGS with extrarenal involvement of other tissues. To date, there are 24 genes associated with FSGS that follow Mendelian patterns of inheritance: autosomal recessive (AR), autosomal dominant (AD), and X-linked; as well as inheritance of mitochondrial DNA. Although most genes have been identified in autosomal recessive forms, six genes have been involved in the rare autosomal dominant (AD) forms of the disease (WT1, LMX1B, ACTN4, TRPC6, INF2, ARHGAP24), some of which are associated with various types of extrarenal features [2-6].
In the interesting study by Boyer et al. , linkage analysis and exome sequencing in a family with autosomal dominant FSGS led unexpectedly to an LMX1B coding variant (R246Q) present only in the cases as the cause of the kidney disease. At present, 164 heterozygous LMX1B mutations are reported to cause nail patella syndrome, which was summarized by Boyer et al. . Renal penetrance is incomplete, with 30%–50% of nail patella patients manifesting kidney disease and ∼5% progressing to end stage kidney disease .
Corinne Antignac and her group identified two novel mutations of the LMX1B gene in three unrelated families with AD FSGS with no extrarenal features. As such, the authors concluded that isolated FSGS could be caused by mutations in genes also involved in syndromic forms of the disease and highlighted the need to include these genes in all diagnosis approaches in FSGS.
The above study vividly illustrate the advantage of next-generation sequencing technologies in unraveling the genetic basis of human kidney disease. Genomic technologies are now reaching the point of being able to detect genetic variation in patients at high accuracy and reduced cost. Although this offers the promise of fundamentally altering medicine; still scientists struggle with how to interpret and how to handle the flood and ambiguity of genome-wide data. Having said that, a multitude of surprises and exciting discoveries are still expected with the widespread application of genomic technologies especially in regions of the world that have more limited access to next-generation sequencing capabilities.
- D’Agati V: Pathologic classification of focal segmental glomerulosclerosis. Semin Nephrol 23: 117–134, 2003
2. Barbaux S, Niaudet P, Gubler MC, Grünfeld JP, Jaubert F, Kuttenn F, Fékété CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K: Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet17: 467–470, 1997
3. Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodríguez- Pérez JC, Allen PG, Beggs AH, Pollak MR: Mutations in ACTN4, encoding alpha-actinin- 4, cause familial focal segmental glomerulosclerosis. Nat Genet 24: 251–256, 2000
4. Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, Daskalakis N, Kwan SY, Ebersviller S, Burchette JL, Pericak- Vance MA, Howell DN, Vance JM, Rosenberg PB: A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308: 1801–1804,2005
5. BrownEJ,SchlöndorffJS,BeckerDJ,Tsukaguchi,TonnaSJ,UscinskiAL,HiggsHN,Henderson JM, Pollak MR: Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet 42: 72–76, 2010
6. Akilesh S, Suleiman H, Yu H, Stander MC, Lavin P, Gbadegesin R, Antignac C, Pollak M, Kopp JB, Winn MP, Shaw AS: Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J Clin Invest 121: 4127 -4137, 2011
7. BoyerO,WoernerS,OakeleyEJ,LinghuB,GribouvalO,TêteMJ,Duca JS, Klickstein L, Damask AJ, Szustakowski JD, Heibel F, Matignon M, Baudouin V, Chantrel F, Champigneulle J, Martin L, Nitschké P, Gubler MC, Johnson KJ, Chibout SD, Antignac C: LMX1B mutations cause hereditary FSGSwithout extrarenal involvement. J Am Soc Nephrol 24:1216–1222, 2013
8. Sweeney E, Fryer A, Mountford R, Green A, McIntosh I: Nail patella syndrome: A review of the phenotype aided by developmental biology. JMedGenet 40: 153–162, 200
There is a fascinating editorial on the 'Equity and Economics of Kidney Disease in Sub-Saharan Africa' by Luyckx and colleagues in this weeks Lancet, as part of their series focussing on kidney disease. The statistics bearing out the human/financial cost of ESRD are horrendous.
EXAMPLES OF FRAUD IN MEDICINE AND IN STUDIES INVOLVING RAS INHIBITION IN JAPAN:
Diovan Data Was Fabricated, Say Japanese Health Minister And University Officials
Following a long series of accusations, retractions, and the resignation of a prominent professor, it now is clear that data from a large Japanese study of valsartan (Diovan, Novartis) was fabricated. On Thursday officials at Kyoto Prefectural University of Medicine said that “had patient records been used in their entirety,” the Kyoto Heart Study “would have had a different conclusion,” reported AFB.
Excellent Editorial in the BMJ entitled: Too much Medicine; Too Little Care:
This Editorial makes excellent points about:
1. Redefining diseases such as Hypertension, Diabetes, obesity, hypercholesterolemia, osteoporosis and... CKD as to increase their prevalence...and raise the spectrum of "Epidemics"...!!! More an Epidemic in Diagnosis rather than a true Epidemic of Disease!
2. Redefining thresholds for disease definition leading to medicalisation of normal variations "normality"..."ageing"...etc...
3. Overinvestigating and consequently Overdiagnose; mostly incidentalomas....
4. The above raising concern, anxiety, cost...with little impact on Outcomes.
This Editorial suggests:
1. More Scepticisms from Physicians about changing thresholds.
2. More Scepticism amongts physicians about new definitions of disease
3. More Scepticism about new Guidelines and Recommendations
4. Better use to language and semantics of health and disease:
Use the terms “raised blood pressure” not “hypertension,”
“reduced bone thickness” not “osteoporosis,”
“reduced kidney function” not “chronic kidney disease” when talking with patients.
A debate has been ongoing for a number of years between those who support the KDOQI (2002) and more recently KDIGO (2012) CKD classification and those who argue that the whole concept has considerable shortcomings and flaws:
Main arguments for current classification:
1. Clinically useful
2. Prognostically relevant as eGFR and albuminuria not only reflect ESRD prognosis but also CVD and all cause mortality outcomes
3. Increased CKD awareness
4. Highlights the true scale of the CKD problem worldwide
Main arguments against:
1. Epidemiologically useful but less so clinically
2. Adds little to conventional prognosis markers such as severity of proteinuria, serum creatinine level at presentation and old fashion 1/sCr slope and/or conventional cardiovascular prediction scores such as Framingham Risk Score.
3. Flawed risk prediction analysis lacking validity and usefulness:
4. Microalbuminuria is not sufficient on its own to define CKD 1 or 2.
5. Artificial and clinically irrelevant division of CKD1 and 2 in the absence of the known difference in natural history of CKD 1 versus 2.
6. Overestimation of CKD, as it is epidemiologically primary a fact that up to 30-40% of those >65 years of age have a "physiological" decline in GFR. Lack of age consideration in the classification. (http://www.ncbi.nlm.nih.gov/pubmed/22437416)
7. Scare mongering of an "epidemic' of CKD based on flawed epidemiological studies
also see lecture on OLA given at the World Congress of Nephrology:
Recent controversy between two extremely knowlegeable and respected camps in this field was highlighted by respective articles in
Clin Chem Lab Med July 2013 by:
Delanaye and Cavalier: http://www.ncbi.nlm.nih.gov/pubmed/23729625
arguing against the status quo
Zoccali and colleagues arguing for the status Quo:
OLA and the Global Kidney Academy encourages a debate on this very important issue in Nephrology.
Taking sides may be unhelpful but more importantly comments are welcomed from practicing Nephrologists on, after evaluating the arguments above:
1. Whether a division between CKD 1 and 2 is justifiable?
2. eGFR and Albuminuria are unique predictors of outcomes in CKD thus justifying their inclusion in classification (KDIGO 2012)
3. Whether Age is irrelevant to classification so should not be taken into consideration?
We need to hear the voice and opinion of Practicing Nephrologists Worldwide!
Targets, trends, excesses, and deficiencies: refocusing clinical investigation to improve patient outcomes.
Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
Clinical trials in nephrology have focused on achieving targets, supplementing deficiencies, and correcting excesses in order to improve patient outcomes. The majority of interventions have failed to demonstrate benefit and some have caused harm. It may be that therapies aiming to 'normalize' parameters may actually disturb evolutionary adaptation, thus causing harm. By refocusing on the physiology of disease, and complexity of adaptation, we may design better trials. We review successful and unsuccessful trials in nephrology and other disciplines and suggest a set of principles by which to design future clinical trials:(1) acknowledge heterogeneity of chronic kidney disease populations and appropriately characterize populations for studies; (2) develop better validated biomarkers (through proteomics, genomics, and metabolomics) to identify responders and nonresponders to interventions; (3) design interventions that mimic physiological processes without collateral detrimental effects; (4) reconsider the status of the randomized-controlled trial as the only 'gold standard' and perform large-scale pragmatic trials comparing current care with the intervention(s) of interest, and (5) broaden nephrology research culture so that the majority of patients are enrolled into observational cohorts and intervention studies, which foster greater knowledge acquisition and dissemination. Improved understanding of pathophysiological mechanisms, in conjunction with more innovative but stringent clinical trial design, will ultimately lead to improved patient outcomes.
This is a very important review of the state of clinical investigation and trials in Nephrology.
It highlights discrepancies betwen between observational and cohort studies and randomised control trials (RCTs); whereby the former often points to interesting associations suggesting interventional studies that ultimately prove consistently negative!
The authors explore potential reasons and explanations for such an intervention "gap".
They highlight the heterogenity of CKD patients, the lack of adequate surrogate markers that predict reliably hard endpoints.
They suggest that a better understanding of the pathophysiology that underpins clinical investigation may mitigate the consistent disappointment generated from interventions based on delusionary endpoints and modifiable parameters.
Finally, they question the place of the RCT as the "only gold standard" and put forward well condcuted pragmatic studies.
In my mind, the problem with Nephrology trials is that they deal with a heterogeneous and also very complex and MULTIFACTORIAL conditions.
Consequently, it is naive to expect that the modification of a single parameter:
Anemia, PO4, PTH, FGF23, BP, LIpids, etc...would suffice to reverse the relentless trend towards increased mortality.
It is high time to consider MULTIFACTORIAL therapies for a MULTIFACTORIAL disease.
It is high time to use combined therapies pitched against standard practice. This has been implemented in diabetes and diabetic nephropathy with some promise (http://www.ncbi.nlm.nih.gov/pubmed/18256393).
The issue and opposition for such an approach will come from the Pharmaceutical industry that dictates the terms and conditions of most clinical investigation in Nephrology and medicine in general.
The Pharmaceutical industry is there to promote ONE compound and not a multifactorial approach that would blur the impact of a given agent and subsequently blur their marketing strategy....
Also, Pharma rush to success leads clinical investigations in Nephrology to rely on soft and often inappropriate surrogate markers instead of taking the time (and cost) of aiming at altering hard endpoint ssuch as morbidity and mortality.
Alternate sources of funding of clincial investigation in Nephrology is key to the success of therapies and intervention in nephrology.
Government agents and NGOs need to take the lead and support clinical investigations that rely on:
1. Hard enpoints to improve patients outcomes.
2. Systematic Observational cohort studies involving more than one centre and more than one country.
3. Clinical investigations that pay attention to socio-demographic and geographic variability; involving emerging countries and their CKD/ESRD patients.
4. Moving away from statistical manipulation of data to serve commercial purposes
5. Moving away from soft and delusional surrogate endpoints
6. Moving away from the obsession with albuminuria reduction; another inappropriate and misunderstood surrogate marker
Ultimately, Nephrologists need to improve their understanding of piublished clinical investigations:
1. Improve their critical appraisal skills
2. Understanding that Proof of Concept (pahse2) trials are NOT conclusive
3. Understanding that subgroup and posthoc analyses are NOT conclusive; instead hypothesis generating
4. Improve their own data collection
5. Improve their own observational skills
It will take time, but a critical evaluation of the state of Clinical Investigation in Nephrology, as undertook by Levin and her colleagues, is timely and should encourage us all to re-think investigations and treatment strategies. This will ultimately translate into tangible and real improvement in patients outcomes. It will also lead to avoidance of harm!