## User blog: Meguid El Nahas

Anyone in the world

Prof Pierre Delanaye wrote a BLOG in OLA French:

www.ncbi.nlm.nih.gov/pubmed/23689071

Une étude purement observationnelle mais intéressante car spécifique aux patients insuffisants rénaux (même si la définition retenue pose un peu problème, à savoir une GFR estimée inférieure à 60 ml/min et/ou une protéinurie). Les auteurs ont comparé la prévalence du contrôle de l'HTA définie sur base d'une mesure en consultation inférieure à 140/90 ou à 130/80 ou sur base d'un monitoring de 24h avec une définition à 130/80 ou 120/75. L'hypertension blouse blanche est définie comme une HTA plus importante en consultation et une HTA masquée si c'est l'inverse (TA contrôlée en consultation mais pas sur holter de 24h). 14382 sujets espagnols ont été recrutés. 8689 n'avaient pas d'IR 72,6% étaient traités (la moitié avec plus de deux médicaments). L'utilisation et le nombre d'antihypertenseurs augmentent avec la progression de l'IR ce qui n'est pas trop étonnant. 21.7% des patients avec IRC ont une TA controlée en consultation (140/90) mais 43.5% ont un holter avec cible inf à 130/80. Le controle de la TA sur holter de 24 h ne semble pas trop différent selon le stade d'IR sur pour le controle de l'HTA nocturne qui augmente avec l'IR

Ce qui est surtout intéressant c'est la concordance entre les résultats du ciontrôle de l'HTA selon que l'on considère la prise en consultation et le monitoring de 24H chez les IRC:
14.7% des sujets sont controlés et sont concordants entre les 2 techniques
49.5% sont concordants pour une marque de contrôle de la TA
Une HTA de la blouse blanche est présente dans 28.8%
Une HTA masquée est présente dans 7% des cas
36% des sujets avec une HTA en consultation présente en fait un effet blouse blanche et 32% des patients controllés en consultation ont en fait une HTA sur le monitoring

=> intéret du monitoring en cas d'IRC?

IN ENGLISH:
Comparing BP control in office with 24h ABPM in CKD patients:
14.7% of individuals are hypertensive by both methods/measurements.
36% white coat hypertension NOT present on 24hABPM
32% normotenive in office but hypertensive over 24h

HOW TO BEST MONITOR BP CONTROL IN CKD?

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

Anyone in the world

Nephrol Dial Transplant. 2013 Oct;28(10):2553-69. doi: 10.1093/ndt/gft214. Epub 2013 Jun 4.

# Cost of peritoneal dialysis and haemodialysis across the world.

### Source

International Renal Research Institute Vicenza (IRRIV), San Bortolo Hospital, Vicenza, Italy.

### Abstract

Peritoneal dialysis (PD) as a modality is underutilized in most parts of the world today despite several advantages including the possibility of it being offered in the remotest of locations and being significantly more affordable than haemodialysis (HD) in most cases. In this article, we will compare the cost of HD and PD in several countries to demonstrate that PD is less than, or at least as expensive as, HD. A thorough literature survey of EMBASE and PUBMED was conducted; 78 articles which compared the annual PD and annual HD costs were finally selected. Careful attention was paid to the methodology followed by each study and the year it was published in. Our final calculations included 46 countries (20 developed and 26 developing). We found that the cost of HD was between 1.25 and 2.35 times the cost of PD in 22 countries (17 developed and 5 developing), between 0.90 and 1.25 times the cost of PD in 15 countries (2 developed and 13 developing), and between 0.22 and 0.90 times the cost of PD in 9 countries (1 developed and 8 developing). From our analysis, it is evident that most developed countries can provide PD at a lesser expense to the healthcare system than HD. The evidence on developing countries is more mixed, but in most cases PD can be provided at a similar cost where economies of scale have been achieved, either by local production or by low import duties on PD equipment.

#### KEYWORDS:

continuous ambulatory peritoneal dialysis (capd), economic analysis, economic impact, haemodialysis, peritoneal dialysis

COMMENTARY:

This very interesting analysis of the cost of HD versus PD worldwide is very revealing. It shows that most Developed countries favor HD over PD as judged by the prevalence of the modalities in their RRT population; USA 93% HD versus 7% PD (1).  The uptake of PD in Europe is marginally better but remains much lower than HD with for instance Germany having as few as 5% of its ESRD patients treated by PD! This, in spite of a higher cost for HD compared to PD; in the US for instance the annual patient cost for HD is around $87,500 compared to$66,750 for PD. It has been estimated that the US, that spends 18% of its GDP on healthcare, could save up to \$1.1 billion over 5 years if the uptake of PD increased from 7% to 15% (2).

Yet there are obstacles to PD utilization in the West including: 1. Reimbursement policies (in France and Germany for instance reimbursement for HD is much higher than that for PD), 2. Physicians/Nephrologists preference, 3. Physicians familiarity with PD; a modality with which they may have little experience, 4. Patients’ preference, 5. Patients’ increasing age and dependency as well as isolation making thrice weekly HD not only a medical but also a social necessity.

The analysis under discussion paints a different cost analysis for PD in Developing countries where in the most deprived, low economies, PD is a more expensive RRT modality than HD! This has many root causes including: 1. the cost of importing PD solutions and related delivery system, 2. PD companies monopoly of pricing, 3. High export duties on such material, all combining to make PD more expensive, in some countries like Egypt 5 times more expensive [HDD/PD cost ratio = 0.22], than HD! Consequently, in Africa for instance, PD utilization is very low or non-existent outside of South Africa, where solutions can be manufactured locally bring the PD cost well below that of HD (3). Hong Kong has the highest PD utilization in the World (80%) due to the low cost of consumables and solutions (PD is half the cost of HD) as well as the PD first policy adopted in this country.

The way forward for low economy countries is to have PD as an economically viable option for RRT. For that they would have to reduce the cost of PD solutions (bags) cost considerably by:

1. Imposing more acceptable prices and breaking the monopolies of major suppliers.
2. Reducing import duties on bags (as has been done in Nepal and Malaysia).
3. Considering the local production of Bags and PD solutions (South Africa and India).
4. Negotiating import contracts with other developing countries that manufacture PD bags and solutions.
5. Encouraging a PD first approach as promoted by Hong Kong and recently adopted by Thailand.

This may offer emerging countries with hardly any RRT due to unaffordability, the option of a potentially cheaper RRT modality compared to HD, thus also bypassing the cost of setting up HD units with the inherent infrastructure cost.

PD first may be, with renal transplantation as soon as possible may be a model to consider. Iran has increased considerably since 1995 its utilization of PD (manufactured locally) (4) as well as its rate of renal transplantation through a concerted centralized healthcare policy. In low and middle economies where ESRD is often a death sentence due to the lack of affordable RRT modalities, Governments have a duty to explore and provide affordable RRT options in order to comply with the moral ethics of the Istanbul Declaration banning organ trafficking. Unless, this is provided, human nature will prevail and organ trafficking will continue out of the despair of some and the greed of others…

References:

2. http://www.ncbi.nlm.nih.gov/pubmed/?term=neil%2C+guest%2C+wong
3. http://www.ncbi.nlm.nih.gov/pubmed/22641735
4. http://www.ncbi.nlm.nih.gov/pubmed/20628104
[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world
##### They showed that what mattered in terms of Cardio-Protection was BP REDUCTION. They reported a reduction of Major Adverse Cardiovascular Events (MACE) by a SIXTH for every reduction of SBP of 5mmHg, regardless of the class of antihypertensive agent used. They showed equal cardioprotection in CKD and non-CKD patients and the level of cardioprotection was not affecetd by the severity of CKD. They also failed to show that more intensive BP control levels had advantages over standard BP control targets.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789583/pdf/bmj.f5680.pdf

This comprehensive and well conducted meta-analysis confirms my long held bias that cardio-protection relies primarily on lowering BP regardless of the agent used. This was also the conclusion of a number of studies and meta-analysis including ALLHAT and the Meta-Analysis of Casas and colleagues in ther Lancet a number of years ago. http://www.ncbi.nlm.nih.gov/pubmed/16338452

We are often referred to the seminal study HOPE arguing that the cardioprotection conferred by RAS inhibitors is independent from their BP lowering effect and is a class specific effect that justifies their use above other anti-hypertensive agents in those at CV risk: http://www.ncbi.nlm.nih.gov/pubmed/10675071

This Mantra...like many in Nephrology has been repeated over and over again by Nephrologists keen to do their best for their patients and egged on by the Pharmaceutical Industry keen to do its best for its shraeholders....and the story went on for more than a quarter of a century inspite of dissending voices questioning the dissociation of the protective effect from the anti-hypertensive effect of RAAS inhibitors. I personally questionned that myth as far back as 2000: http://www.ncbi.nlm.nih.gov/pubmed/10754405

The confusion and issues are due to a number of reasons:

1. Pharma Industry hold of Key Opinion Leaders and Clinical Trialists over the last quarter of a century. I recollect conducting a study on progression comparing Lisinopril versus Placebo (with equal BP control) in the late 80s and study impact on progression: Result: NO difference. Outcome: Never Published...???!!!!

2. Lack of Critical Reading or Appraisal skills by most of those of us who read published material and Clinical Trials Reports; most dont bother to read the methodology section; abstracts or even title is often enough to embrace a new idea...treatment...or myth...and run with it!

3. Physicians commercialism; always keen to impress (and hence charge more...) patients with the latest treatments stemming from the latest publications even if they half understand their scientific implications as long as they fully understand their financial incolme generation implication.

4. MOST IMPORTANTLY....the alleged dissociation between the cardioprotective effect of RAAS inhibitors from their anti-hypertensive effects stems to a large extent from the fact that BP is RCTs (Clinical Trials) is seldom measured correctly; often if not invariably relying on causal office BP reading after a few minutes of rest...this is the least valuable, accurate or predictive method in terms of CVD outcomes as nocturnal, day:night and 24h Ambulatory BP measurement (ABPM) have proved much more reliable and predicitve.

In fact and of relevance, is the observation of a HOPE sub-study itself by Svensson et al (2001) who compared office BP and 24h ABPM and concluded: "Although, OBP is the correct comparator when comparing with previous large intervention trials and epidemiological studies, the effects on cardiovascular morbidity and mortality seen with ramipril in the HOPE study may, to a larger extent than previously ascribed, relate to effects on blood pressure patterns over the 24-hour period" .

http://www.ncbi.nlm.nih.gov/pubmed/11751742

So to conclude:

What seems to matter in the cardioprotection of CKD pateints is good BP control (KDIGO recommends <140/90mmHg) with due consideration to patients age and co-morbidities, this regardless of the class of antihypertensive agents used. Considerations should be then given to patients tolearbility, Risk versus Benefits of a given clkass of agents as well as Cost : Benefit ratio in countries where patients have to pay for their medication; a factor that greatly impacts on compliance and quality of BP control.

Finally, let us not forget that even in the US the majority of those with Hypertension are either NOT treated or POORLY CONTROLLED:

http://www.ncbi.nlm.nih.gov/pubmed/19710486

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

Anyone in the world

After years and even decades of total neglect, the Nephrology community is waking up to the fact that Creatinine Clearance is affected by  Tubular Secretion of Creatinine (TSCr)...!!!

A recent article in the September 2013 issue of the Am J Kidney Disease by Sithoven and colleagues in Groningen, Netherlands shows that there is a good agreement in ADPKD between eGFR and measured GFR (mGFR) in individuals with normal renal function highlighting the fact that at normal eGFR range, tubular secretion (TS) Creatinine (TSCr) is relatively small and therefore doesnt confound estimation of kidney function by eGFR (MDRD or CKD EPI). They also argue that such correlation was maintained in a subgroup of patients followed-up for 3 years.

This somehow disagrees with teh observations of Rugennenti and his colleagues in Bergamo who showed poor agreement between eGFR and mGFR in estimating the rate of decline in kidney function in ADPKD and that both MDRD and CKD EPI failed to accurately detect changes in mGFR in those with ADPKD and declining renal function. This, in spite of a comparebale baseline GFR to that of the Groningen group at the onset but a significant rate of decline with time of around 8-10ml/min.

The discrepancy between the two articles highlight the fact well know to Nephrologists for the last century or so that the Tubular secretion of Creatinine is relatively small in normal GFR ranges but increases significantly as GFR declines to reach as mush as 50% of Creatinine Clearance when GFR is <20-30ml/min.

Therefore, eGFR is most likley to be useless in the evaluation of interventions aimed at impacting on the rate of GFR progression as when true GFR declines tubular secretion of creatinine increases confounding the use of serum creatinine as a parameter of progressive CKD.  So whilst Spithoven et al are right in their statement that eGFR is accurate in evaluating true measured GFR in ADPKD, the difference between the studies and their resepctive and contradictory assertions may lay in the level of GFR and the rate of decline of kidney function; lower GFR and faster rate of GFR decline leads to increased tubular secretion of creatinine and consequently decreased agreement between measured and calculated GFRs.

This was also reported by Gaspari et al, 2013 in T2DM where formulated GFR underperformed and underestimated the rate of true GFR decline.

This again highlights the fact that TSCr cannot be ignored including in diabetes mellitus where changes in tubular secretion of creatinine have been reported due to the impact of diabetes on proximal tubules transporters of creatinine and changes related to impaired kidney function and metabolic control. Too many confounders for serum creatinine to be an accurate marker of glomerular filtration.

Furthermore, interventions themselves may impact on the tubular handling and secretion of creatinine and consequently making interpretation of the intervention of rate of decline of GFR impossible. Incidentally, this is the case with RAS (renin angiotensin system) inhibition that has been show both experimentally and clinically to improve tubular secretion of creatinine in diabetic nephropathy confounding ANY conclusions on the impact of RAS inhibitors on the decline in eGFR in diabetic nephropathy:

In conclusion:

All the studies on the progression of CKD relying on measurements and changes in serum creatinine levels or the changes in formulated/estimated GFR (eGFR) are likely to be inaccurate due to the major confounding effect of Tubular Secretion of Creatinine. Not withstanding the additional confounder of the impact of any given intervention on Tubular Secretion of Creatinine. The BEAM/BEACON studies are tragic reminders of the unreliability of eGFR in interventions with agents that impact on tubular viability and function and consequently impact on serum creatinine/eGFR through mechanisms unrelated to changes in GFR.

Sadly and disappointingly, to date I am not aware of a single intervention study in CKD where GFR was measured serially to asses progression in the entire study population (with the exemption of the MDRD study in 1994 where iothalamate clearance was used throughout the study period).

Reliance on eGFR to test interventions that may slow the progression of CKD is a tragic and often wilful mistake.

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

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

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 ]

Anyone in the world

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

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

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 ProfTerukuni 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.

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 ]

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 ]

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:

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 ]

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!

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

Anyone in the world
[ Modified: Thursday, 1 January 1970, 1:00 AM ]