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Picture of Meguid El Nahas
by Meguid El Nahas - Wednesday, 4 September 2013, 6:46 PM
Anyone in the world

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. 

http://www.ncbi.nlm.nih.gov/pubmed/?term=anticoagulation%2C+Cystatin%2C+creatinine

Comments: 

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....

 

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

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    Anyone in the world

    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) [1].

    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. [7], 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. [7]. Renal penetrance is incomplete, with 30%–50% of nail patella patients manifesting kidney disease and ∼5% progressing to end stage kidney disease [8].

    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. 

     

    References

    1. 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

     

      

     

     

     

     

      

     

    [ Modified: Thursday, 1 January 1970, 1:00 AM ]

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      Picture of Arif Khwaja
      by Arif Khwaja - Sunday, 14 July 2013, 9:20 PM
      Anyone in the world

      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.

      Data is presented from Nigeria reporting a median survival of 2 weeks in 760 patients presenting with ESRD with only 6·8% able to continue for more than 12 weeks - invariably bankrupting their families in the process. PD and transplantation are not widely available and again the cost of the fluids seem to preclude the widespread use of PD whilst the infrastructure required to build a transplant program is not there in most countries. 
      The authors highlight a number of key issues:
       
      i) the scale of the problem of CKD and ESRD is simply unknown in most Subsaharan countries making service planning almost impossible
       
      ii) the need to identify and treat kidney disease early in those at high risk of kidney disease - in part this will involve a strategy dealing with non-communicable diseases such as diabetes and hypertension. These can be delivered cheaply by trained healthworkers rather than more expensive doctors as was shown in Iran.
       
      iii) finally the authors call for a strategy to treat those who develop ESRD - the need to develop an infrastructure for transplantation and the need for dialysis. This of courses raises important questions of equity - is it worth funding RRT in such resource-poor environments when the cost in countries such as  Malawi, is almost 1000 times the national per-head health expenditure and 65 times the gross national income per head.
       
      There are a few other points that aren't discussed that are perhaps also worth considering:
       
      i) even within Sub-saharan Africa that are significant variations in care that can't be explained by money. For example the GNP per capita for Nigeria and Sudan are broadly similar and less than $2000. Yet Sudan has been able to provide RRT for its population - this must reflect political decision making and prioritisation.. I was fortunate to hear Professor Abu Aisha ( nephrologist and ex minister of health in Sudan) give an inspirational talk a few months ago about how nephrology (and healthcare in general) were transformed in a low-resource setting when the political will is there.
       
      ii) clearly prevention is the key -managing non-communicable disease, improving obstetric care and infectious disease management, preventing and treating HIV will all impact on the numbers with ESRD. i.e. its essential that resources arent nephro-centric but rather focussed on key public health areas which in turn feed the ESRD epidemic. And of course spending money on eduction, sanitation  and clean water supply will all positively impact in public health in general as well as ESRD and CKD numbers
       
      iii) whichever way you look at the problem you cant divorce it from politics and economics. The Nobel Prize winning economist Joseph Stigilitz has highlighted Mauritius as an example of country whose healthcare system has been transformed as a result of political decisions. Public health policy is de facto political and clinicians shouldn't shy away from getting involved in controversial political debates.
       
      iv) there has to be an onus on industry and academia to come up with cheap, technological solutions for RRT. Cheap fluid for PD, aggressive transplantation, a cost effective model for dialysis are all areas of urgent research.
       
      v) Like myself both the first and senior author of this paper are not primarily based in Africa  ( the middle author is Prof Naicker, a nephrologist from South Africa) but in a high-income western economy. This in itself is a problem. Journals such as the Lancet should perhaps try to provide a platform for African clinicians to come up with local solutions  and models of care. I hope some of the OLA readers working in Sub-Saharan Africa will educate me on what needs to be done......
      [ Modified: Thursday, 1 January 1970, 1:00 AM ]

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        Picture of Meguid El Nahas
        by Meguid El Nahas - Sunday, 14 July 2013, 10:28 AM
        Anyone in the world

        EXAMPLES OF FRAUD IN MEDICINE AND IN STUDIES INVOLVING RAS INHIBITION IN JAPAN:

        July 12, 2013

        Diovan Data Was Fabricated, Say Japanese Health Minister And University OfficialsReply

        by Larry Husten • People, Places & EventsPolicy & Ethics • Tags: Hiroaki MatsubaraJapan,KyotoKyoto Prefectural University of MedicineNovartisscientific misconductvalsartan

         

        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.

        In 2009 the Kyoto Heart Study investigators, including the chief investigator, Hiroaki Matsubara, reported that treatment with valsartan resulted in significant cardiovascular benefits independent of the drug’s blood-pressure lowering effect. Now officials at the university say the drug had no such effect.

        On Friday Norihisa Tamura, Japan’s health minister, said data had been “fabricated and falsified.” Tamura said he would set up a committee to prevent episodes like this from happening again.

        and in the past:
         

        RETRACTED: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial

        Dr Naoyuki Nakao MD a Corresponding AuthorEmail AddressAshio Yoshimura MD aHiroyuki Morita MD aMasyuki Takada MD bTsuguo Kayano MD bProfTerukuni Ideura MD a

        Summary

        Background

        Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease. We aimed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker, and monotherapy of each drug at its maximumdose, in patients with non-diabetic renal disease.

        Methods

        336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan. After screening and an 18-week run-in period, 263 patients were randomly assigned angiotensin-II receptor blocker (losartan, 100 mg daily), angiotensin-converting-enzyme inhibitor (trandolapril, 3 mg daily), or a combination of both drugs at equivalent doses. Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease. Analysis was by intention to treat.

        Findings

        Seven patients discontinued or were otherwise lost to follow-up. Ten (11%) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 (23%) of 85 on trandolapril alone (hazard ratio 0·38, 95% CI 0·18—0·63, p=0·018) and 20 (23%) of 86 on losartan alone (0·40, 0·17—0·69, p=0·016). Covariates affecting renal survival were combination treatment (hazard ratio 0·38, 95% CI 0·18—0·63, p=0·011), age (1·30, 1·03—2·29, p=0·009), baseline renal function (1·80, 1·02—2·99, p=0·021), change in daily urinary protein excretion rate (0·58, 0·24—0·88, p=0·022), use of diuretics (0·80, 0·30—0·94, p=0·043), and antiproteinuric response to trandolapril (0·81, 0·21—0·91, p=0·039). Frequency of side-effects with combination treatment was the same as with trandolapril alone.

        Interpretation

        Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary endpoint on combined treatment, further strategies for complete management of progressive nondiabetic renal disease need to be researched.
         
        Comments:
         
        These are very disturbing reports of fraudulent publications in Japan relating to the efficacy and superiority of RAAS inhibitors whether Trandolapril in combination with Losartan on the progression of CKD (Nakao et al) or the Kyoto Heart Stduy on Valsartan cardioprotective effects independlently of changes in BP...so why is this taking place in Japan but undoubtedly elsewhere.
         
        Back to Bad Pharma...and Bad Doctors....but alo Japan...
         
        Most clinical traisl of new therapeutic agenst are sponsored by the Pharmaceutical Industry; Good Pharma, without it we wouldnt be treating many life threatening medical conditions.
         
        But
        1. Most clinical investigators in many emerging (and emerged as well...) countries are targeted by the Pharma industry; they are receiving remunarations for their involvement in such clinical trials; in the form of money, in the form of recognition, in the form of prominence and fame in their profession...doctors like all humans are responsive to such incentives...
        Consequently, doctors and invetigators involved in clinical trials want to please their paymater...the Big Pharma who recruits them.
         
        2. Pharma analyses the result of the RCTs they sponsor....statisticians and analysts employed by the Pharma company almost exclusively analyse the result and data of the study; they "clean" it..."process"...it and ultimately provide investigators with a sanitised version of the outcome of the trial...
        This is dangerous as it invites manipulation of the data by the Pharma employees to please their paymaters....Bad Pharam!
        This has come to light in the UK with a major Pharma company in a trial on osteoporosis where the raw data emanating of the trial were not shown or shared with the investigators but instead the sanitised version of the Pharma analysis leading to questions posed by the likes of Dr Aubrey Blumsohn (who wasnt paid by them) about the conduct of senior investigatores including Prof Richard Eastell (who was a senior consultant to the Pharma):
        http://www.bmj.com/content/339/bmj.b5293
         
        3. Next, why are these fradulent reports emanating repeatedly from Japan?
        This brings to mind issues relating to Japanese culture, and the deferential approach to authority and seniority. 
        Dont challenge, dont question...authority; If the Professor says that the trial is positive....who is the junior investigator or company employee to challenge him (seldom her...). Whistleblowing is not yet part of japanese culture. Whistelblowers are fired...marginalised or even prosecuted...this was highlighted in the report by Michael Woodford, who was the Olypmus camera company Chief Executive Office (CEO), who reported alarmingly bad and fraudulent practices in the Japanese company he was head of; he was fired and sued by the company! he wrote "EXPOSURE" counterattacked and got vindicated as bad and fraudulent practices were confirmed and the company found guilty of malpractices...
        He wrote a book: "EXPOSURE" that puts the fraudulent practice of Olympus in the context of the Japanese society and its culture. he attributed malpractices in Japan industry to over-deferential attitude to authority and seniority. This may also be symptomatic of japanese healthcare companies and medical investigations.
         
        WHISTELBLOWING IS HEALTHY AND OFTEN JUSTIFIABLE....BUT THE WHILSTLEBLOWER SHOULD BE WILLING TO PUT HIS JOB ON THE LINE AS DR AUBREY BLUMSOHN AND MR MICHAEL WOODFORD DID...they both rendered a huge service to probity and transparency in Pharma and Industry in general!
         
        BIG PHARMA needs to think again the conduct of their clinical trials....BAD DOCTORS need to be checked and challenged by those working with them and collaborating in their clinical investigations worldwide...as Scientifc Fraud is not a Japanese Exclusive....it is prevalent worldwide:
        This is very nciely reviewed in this BMJ paper,  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702092/?report=classic,
        listing:
        Lack of Ethics
        Career Ambitions/Promotion
        Financial Rewards
        Academic and Professional Rewards
        But also Lack of Institutional monitoring and vigilance
         
        A Must read for all clinical investigators!
        [ Modified: Thursday, 1 January 1970, 1:00 AM ]

        Comments

           
          Picture of Meguid El Nahas
          by Meguid El Nahas - Wednesday, 10 July 2013, 12:33 PM
          Anyone in the world

          Excellent Editorial in the BMJ entitled: Too much Medicine; Too Little Care:

          http://www.ncbi.nlm.nih.gov/pubmed/23820022

          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.

          5. Better sharing with the Public of the uncertainty and significance of the findings as well as the risk, benefits and cost of screening and redefining   diseases.
          This applies to CKD as much as any other "disease", with clear healthcare implications including an increasing overlooking of true CKD (that is referred CKD of patients with glomerulonephritis, vasculitis, interstitial nephropathies, heriditary diseases etc...) whilst more attention and probably manpower and resources are diverted to:
          1. Looking/Screening for "CKD" in communties...it has become an obsession...in our profession!?
          2. Early detection of CKD...with little insights into potential harm...and known benefit...?!
          3. The growing "Epidemic" of CKD... which seems related to an "Epidemic" of Diagnosis and eGFR formulas rather than a true change in the number of people with progressive CKD or ESRD; the latter if anything may be coming down rather than increasing!
          4. The Medicalisation of Normality; decline of kidney function with age...?!
          We have to ask ourselves:
          WHY?
          WHO has a vested interest in such "Epidemic of CKD"
          The answer seems manifold:
          The Profession: Increasing its profile; from a small subspecialty of Medicine to a Global Healthcare Challenge!
          http://www.ncbi.nlm.nih.gov/pubmed/23727165
          Nephrologists: More Research into a new disease, a growing disease, a major threat...more grants, larger departments, more income generation...more publications, etc...Academic Recognition?!
          Market factors: More disease, More Patients, More Consultations, More Income...?!
          Pharma: More Disease, More Patients, More Treatments, More Income...?!
          All very intriguing but happening in CKD, which would be acceptable if HARMLESS, but of considerable of concern if HARMFUL!
           
           
          [ Modified: Thursday, 1 January 1970, 1:00 AM ]

          Comments

             
            Anyone in the world
            There is an interesting paper published in this weeks NEJM by Suthanthiran and colleagues evaluating the predictive value of urinary biomarkers in acute cellular rejection. They collected 4300 urine samples from 485 kidney grafts from day 3 post-transplantation to 12 months. They measured absolute levels of  urinary mRNA of CD3e, perforin, granzymeB, proteinase inhibitor 9, CD103, Inteferon-inducible protein -10 (IP-10), CXCR3 and TGF-beta1 and 18S ribosomal RNA (rRNA). They came up with a three gene signature of CD3e, IP-10 and 18S rRNA to discriminate acute cellular rejection from those not displaying rejection.
            They demonstrated an area under the curve (AUC) of 0.85, p<0.001 by ROC curve analysis for this three gene signature discriminating aucte cellular rejection from non-acute cellular rejection. In the external data validation set the AUC was lower at 0.74 though this apparently wasnt significantly different from the AUC in the primary data set. Interestingly in sequential urine samples there was a significant incraese in the 3 gene signature in the 30 days prior to the development of acute rejection, raising the possibility that this signature could be used to identify incipient patients who are about to develop rejection. There is a long history of groups looking for non-invasive markers of rejection (either for mRNA or a proteomic approach) and this is certainly an interesting addition to that literature.
            The statistical methodology in this paper is complex and is beyond my area of expertise but my immediate thoughts are:
             
            i) is an AUC of 0.74 to  0.85 really good enough for a diagnostic test? Probably not!
            ii) In an era of daycase US-guided renal biopsies are we overplaying the risk of transplant biopsies? The risks of biopsies are small (but not zero) and its not clear to me that there is a clinical need to replace a gold-standard test with a non-invasive test. A biopsy will of course provide other invaluable therapeutic information such as evidency of viral infections and drug toxicity which maybe difficult for a non-invasive test to do.
            iii) the increase in the trajectory of the gene signature prior to the diagnosis of rejection is interesting as it raises the tantalising possiblity that such an approach may help diagnose rejection earlier. However no comparative data is presented to show what happened to either GFR or creatinine in the 30 days prior to the diagnosis of rejection. i.e. the paper didnt really answer the question whether this test was any better than measuring the serum creatinine
            iv) clearly prospective studies in other data sets comparing to conventional measures of graft dysfunction will be helpful- till then I think this kind of approach to diagnosing rejection has a long way to go
             
            [ Modified: Thursday, 1 January 1970, 1:00 AM ]

            Comments

               
              Anyone in the world

              CKD Classification:

              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

              http://www.ncbi.nlm.nih.gov/pubmed/20483451

              3. Increased CKD awareness 

              http://www.ncbi.nlm.nih.gov/pubmed/23727165

              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. 

              http://www.ncbi.nlm.nih.gov/pubmed/21811078

              http://www.ncbi.nlm.nih.gov/pubmed/21357908

              3. Flawed risk prediction analysis lacking validity and usefulness:

              http://www.ncbi.nlm.nih.gov/pubmed/23588748

              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

              http://www.ncbi.nlm.nih.gov/pubmed/21965592

              also see lecture on OLA given at the World Congress of Nephrology: 

              http://www.youtube.com/watch?v=P6Tq7_mlNPg

              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 

              and 

              Zoccali and colleagues arguing for the status Quo:

              http://www.ncbi.nlm.nih.gov/pubmed/23828429

              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!

               

               

               

               

               

               

              [ Modified: Thursday, 1 January 1970, 1:00 AM ]

              Comments

                 
                Anyone in the world
                Kidney Int. 2013 Jun;83(6):1001-9. doi: 10.1038/ki.2013.91. Epub 2013 Mar 20.

                Targets, trends, excesses, and deficiencies: refocusing clinical investigation to improve patient outcomes.

                Source

                Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.

                Abstract

                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.

                 

                Comment:

                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.

                Also:

                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

                and also:

                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!

                 

                 

                 

                 
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