## Site blog

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 ]

Anyone in the world

This weeks NEJM sees the publication of 2 open label, phase 2 studies describing the experience of Eculizumab in atypical HUS (aHUS). Eculizumab is a humanised monoclonal antibody that inhibits activation of complement by binding to C5 complement protein thereby preventing the generation of proinflammatory C5a and C5b-9. Eculizumab is licensed for the treatment of paroxysmal nocturnal haemoglobinuria. aHUS is characterised by chronic activation of the complement system as a result of either genetic or acquired defects. (See here for excellent review on complement and aHUS).

All patients with evidence of Shiga-toxin producing E-Coli or low ADAMTS13 activity were excluded from the 2 trials. In study 1, 17 patients were treated if they had i) evidence of progressive thrombotic microangiopathy (TMA) as determined by declining platelet count ii) haemolysis iii) evidence of abnormal kidney function ( median eGFR was 19mls/min/1.73m2 and iv) > 4 plasma exchange/infusion sessions in the week prior to screening. 15/17 patients completed treatment to 26 weeks and another 13 continued through an extension phase. The primary endpoint was change in platelet count though GFR, requirement for plasma exchange and quality of life were also recorded. There was a significant increase in platelet count with 87-88% having normal platelet counts and LDH by 26 weeks ( ie. no significant evidence of TMA and haemolysis), a significant increase in eGFR from baseline to 26 weeks by 32mls/min/1.73m2 and a significant improvement in quality of life at 26 weeks ( not surprising as disease had effectively been controlled for most subjects). 15/17 patients required no further plasma exchange

Trial 2 involved more 'chronic' aHUS patients who were being treated with plasma exchange at least once every 2 weeks (but less than 3x week) for at least 8 weeks. 80% met the primary endpoint (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) and no patients required dialysis or plasma exchange.

In both studies serious adverse events were very common some of which were thought to be drug related including severe hypertension, peritonitis and influenza. All patients received meningococcal vaccination and prophylaxis.

So what does this tell us? Clearly doing an RCT in a rare, acute  and often explosive disease such as aHUS is very difficult and therefore the investigators are to be congratulated on conducting a trial in such a difficult area. The trial confirms that complement dysregulation is a central therapeutic target in aHUS. Whilst Eculizumab has significant toxicity (and the consequences of longterm use are not known), requires repeated infusions on a weekly to 2 weekly basis, aHUS itself has disastrous consequences with upto 40% dying or developing ESRD within the first year of presentation. Furthermore the drug clearly works preventing the need for long term plasma exchange and improving TMA, kidney function but also quality of life. An in vivo assay of complement activity revealed Eculizumab inhibited complement within one hour of infusion. Patients who missed doses of Eculizumab were more likely to develop severe complications of TMA.

So Eculizumab clearly represents a major step forward in the treatment of aHUS. Both the FDA and the European Medical Agency have granted a license for Eculizumab in aHUS. There is obviously huge interest in its use in other complement-mediated disease processes such as MPGN, catastrophic anti-phospholipid antibody syndrome and even antibody-mediated rejection in transplantation. However the real elephant in the room is what is cost - wikipaedia says that Eculizumab costs $600,000 USD per year. In the UK haemodialysis is roughly £30,000 ($45,000) per annum which means that it doesnt compare favourably to dialysis in terms of cost-effectiveness. It is important that research into rare diseases continues and new therapies are developed and clearly those companies that take on such risky projects need to get their 'reward' otherwise others will stop doing research in the area. However this kind of price is prohibitively expensive for most healthcare economies unless a different pricing structure and/or model of funding is developed such as 'performance-related' funding in the UK for the use of bortezomib in myeloma.

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

Anyone in the world

There is increasing interest in frequent haemodialysis (whether nocturnal or daily) as a result of the frequent daily dialysis study which demonstrated that frequent HD was superior to thrice weekly HD with respect to the composite endpoint of death and left ventricular mass. Its worth pointing out here that there was no significant difference in death between the two groups and its perhaps not surprising that LVMI was better in the daily dialysis group given the tighter volume control. One thing that is not mentioned as much is the higher incidence of vascular access problems in the frequent dialysis group. Now a post-hoc analysis of the two FHN trials by Daugiridas in this months Kidney International highlights some important concerns about the apparently deleterious impact of frequent hemodialysis on residual kidney function (RKF). They showed that in the Nocturnal Trial 63 patients had significant RKF at baseline. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared with 18% and 36% in controls. In contrast in the daily dialysis trial dialysis frequency did not impact on RKF - however the range of RKF was narrower in this study and patients with a Kidney urea clearance (Kru) >3ml/min/35 liters estimated body water were excluded which thus may have limited the capacity to detect differences.

Its important not too read too much into such post-hoc analyses, that werent powered to evaluate the impact on RKF. Furthermore there are all sorts of methodological issues with how best to measure KRF as pointed out by Professo Farrington in an accompanying editorial.  However notwithstanding these limitations the study raises important questions that need to be considered -

i) the increasing vogue for frequent dialysis in the literature needs to be tempered by a better understanding of the potential risks such as negative impact on RKF and vascular access. Hypotension, volume depletion, inflammation may all be mechanisms by which frequent dialysis negatively impacts on RKF.

ii) how frequent is frequent and is there a frequency of dialysis (say 4X week) which may offer the benefits of  frequent dialysis without the adverse consequences? clearly we simply dont know the answer to this but like much of the nephrology there probably needs to be a paradigm shift away from uniform therapy for all ( say thrice weekly dialysis) to individualised therapy which takes into account factors such as comorbidity, likelihood of transplantation and RKF. Like many nephrologists I now have some patients on 4 -5 times a week dialysis with others and some only on twice a week dialysis. The thrice weekly standard dialysis prescription maybe suitable for many but certainly not all patients. Thus finding easier ways of measuring RKF may then allow us to individualise therapy appropriately. Trying to get timed collections of urine in patients on dialysis can be fiendishly difficult.

iii) The choice on dialysis seems to be between tight fluid  and BP control (with resulting anuria) or a more 'hydrated' state with better preservation of RKF. Farrington argues that we should be trying to do both but the reality is at the moment we simply have no real idea of how to manage volume in the haemodialysis patient and what we are trying to aim for. Whilst overhydration appears to be harmful and asociated with adverse outcomes defining normohydration is not something we are able to easily do. The Tassin approach to fluid management  may work in Tassin but Im not sure how translatable this is to other clinical settings and populations.Tools such as bioimpedance measurement may help but these have yet to transition from the research arena to the dialysis floor.

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

Anyone in the world

Every time I attend an international mega congress or conference, I cant help reflecting as to the true purpose of these huge agglomeration of doctors, specialists and in our case Nephrologists.

The true education value is at best modest; mostly senior speakers repeating well rehearsed mantras....

Mostly unpublishable free communications and posters....in fact previous studies showed that less than 25% of these free communications or posters ever make it to print due to poor and unpublishable and poor quality; I suspect at some meetings the percentage is even lower...

So perhaps, we should forget CME and look for other benefits...

They are a great opportunity to meet and see some of the good and great of our profession!

They are a great opportunity to meet friends and colleagues and network.

They are a great opportunity to discuss issues, research as well as plan collaborative initiatives.

They are a great opportunity to familiarise oneself with the working of influences within medical societies and their impact on our practice and leadership. Some spend more times in committee rooms than in lecture halls.

They are great opportunity to witness the best and worst of Big Pharma.

They are great touristical opportunities as they are always held in distractingly beautiful cities where there is no competition between staying in door in badly lit conference hall or going out in the glorious sunshine....surely not teh best recipe to keep delegates attending lectures and talks...!!!

PERHAPS, WE SHOULD NOT LOOK FOR EDUCATIONAL VALUE IN THE CONVENTIONAL SENSE BUT LOOK FOR PARALLEL AND ALTERNATE EDUCATIONAL VALUES OF INTERNATIONAL CONGRESSES!

So lets share on OLA the true value of the ERA EDTA congress to those who attended; tell us what you gained from the Congress.

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

Anyone in the world

Attending the 50h Congress of the ERA EDTA in Istanbul. I appreciated how beautiful this city is. I also appreciated or once more realised how important the pharmaceutical industry (Pharma) is to medical conferences, congresses and nephrological education.

Pharma supports heavily, even in times of recession, conferences and their infrastructure.

Pharma also brings planeloads of delegates to attend these meetings.

Pharma organises symposia and workshops.

Pharma is everywhere....great in the first instance with sponsoriships of events, delegates, speakers and social entertainment.

Then I listen to some speakers, attend some sessions and reflect how Pharma has permeated the medical psyche...slowly...insideously but surely....

Speakers who are also often those who have been generoulsy sponsored by Pharma and as Key Opinion Leaders (KOL) have financially been rewarded by Pharma, this has dented their independance, their scientific integrity and their portraying of Pharma sponsored research:

TREAT, EVOLVE, RITUXIVAS, etc....all negative and inconclusive trials....become beacons of hope....for subgroups...if only the poor delegate understood it correctly....that really thery were not negative trials, using potentially dangerous products...but instead hopeful endaveours to improve the lives and health of a small subgroups and sub-sub-groups worthy benefitors of these wonderful and expensive drugs...

I stand up and ask a RCT expert (prof David Jayne) whats the point of RCTs if negative results are discarded and we fall back on anecdotes and the answer is...in Lupus nephritis there has only been two drugs supported by RCTs....so my thought was why bother with RCTs...just dish out Rituximab to everybody and wait to stop more trials such as BELONG due to side effects or design them in such a way that they are underpoewred, like LUNAR, so that they continue to be used with the excuse....that the study was underpowered and the sample size too small....somebody could have told a Pharma company investing hundred of millions of dollars in a RCTs that it was underpowered...perhaps even one of their eminent clinicla advisors generously paid to advise....on RCT design???!!!!

Elegant and elaborate lectures are given to mask lack of evidence; elegance and powerpoint animation replacing and even covering form soft data, lack of evidence and lack of integrity....

Perhaps after all that is the way of medical life and research.

Perhaps, Nephrologists dont know better...

Perhaps, Pharma is smart and nephrologists greedy....

after all we are Nephrologists but also human beings....

BUT A WORD OF WARNING FOR THOSE WHO ATTEND THESE CONFERENCES, DONT LOOSE AS AN AUDIENCE THE POWER OF SKEPTICISM AND CRITICAL THINKING.

It is not because such or such company payed your air fare and put you up in a 5 star hotel that you should leave your integrity as a critical mind at home....!!!!

BE CRITICAL, CHALLENGE AND BE SKETICAL....this way at least you attempt to find some of the truths amongst the Hype!

PS: I declare conflict of interest as I have also been sponsored by Pharma over the years and have as KOL often been generously paid for my participation in pharma advisory boards....!!!

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

Anyone in the world

FDA Limits Duration, Usage of Tolvaptan Due to Possible Liver Injury

ROCKVILLE, Md -- April 30, 2013 -- The US Food and Drug Administration (FDA) has determined that the drug tolvaptan (Samsca) should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially requiring liver transplant or death. An increased risk of liver injury was observed in recent large clinical trials evaluating tolvaptan for a new use in patients with autosomal dominant polycystic kidney disease (ADPKD)

The FDA has worked with the manufacturer to revise the tolvaptan drug label to include these new limitations.

The tolvaptan drug label has been updated to include the following information:

• Limitation of the duration of tolvaptan treatment to 30 days (Dosage and Administration and Warnings and Precautions sections)

• Removal of the indication for use in patients with cirrhosis. Use of tolvaptan in patients with underlying liver disease, including cirrhosis, should be avoided because the ability to recover from liver injury may be impaired (Indications and Usage and Use in Specific Populations sections).

• Description of liver injuries seen in clinical trials of patients with ADPKD.

• Recommendation to discontinue tolvaptan in patients with symptoms of liver injury.

Data Summary

Tolvaptan was approved in May 2009 for the treatment of clinically significant euvolemic and hypervolemic hyponatremia. Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response before subsequently receiving tolvaptan in the outpatient setting.

Tolvaptan is being studied for another indication: delay in progression of renal disease in adult patients with ADPKD. Three cases of serious liver injury attributed to tolvaptan were observed in a placebo-controlled trial in ADPKD and its open-label extension study, indicating the potential for the drug to cause liver injury that could progress to liver failure.

In addition, tolvaptan was associated with an increased incidence of ALT elevations greater than 3 times the upper limit of normal: 42 of 958 (4.4%) patients in the tolvaptan group versus 5 of 484 (1.0%) patients in the placebo group. The serious liver injury cases were consistent with Hy’s law.

Analysis of safety information in the clinical trials that supported the hyponatremia indication (and in other populations such as those with heart failure) did not demonstrate hepatotoxicity. However, the controlled hyponatremia trials were of short duration --about 30 days.

Although the FDA has received spontaneous post-marketing reports of elevated liver enzymes and other liver events in patients taking tolvaptan, these reports are difficult to interpret because many of the patients had underlying disease that can be associated with elevated liver enzymes or liver injury (cirrhosis, heart failure or cancer).

Based on the cases of liver injury in patients participating in the ADPKD trials, the FDA worked with the manufacturer to revise the tolvaptan drug label to include the above information, to reduce the potential for serious liver injury.

Comment:

Another drug bites the dust...and reminds us all that post-marketing surveillance is key to ascertain the safety of new medications.

The TEMPO study of Tolvaptan in ADPKD showed a marginal benefit on CKD progression.

Enthusiasts and those prompted by the sponsor/Pharma claimed a breakthrough in ADPKD management, in spite of the fact that the benefit on CKD progression was minimal (see OLA Blog TEMPO TEMPERED).

So now it seems that whilst the BENEFIT is marginal,  the RISK, side effects, is potentially high.

Back to the drawing board with the management of ADPKD; mTOR antagonists also have a bad/high RISK v BENEFIT profile!

For alternative therapeutic interventions to slow cysts progression and CKD in ADPKD, see the excellent review by Chang & Ong in Nephron:

3 hopeful strategies for ADPKD: 1. reduce intracellular cAMP manipulations, 2. inhibit cell proliferation, 3. reduce tubular fluid secretion.

http://www.ncbi.nlm.nih.gov/pubmed/22205396

Also more mundane interventios such as BP control and RAAS inhibition: HALT_PKD trial: The HALT-PKD study (underway) may tell us all we need to know that to slow the progression of ADPKD we need to optimise BP control...but that combination ACEi + ARB may not be such a good idea after all....this trial may have been overtaken by the negative outcomes of trials of maximum/combined RAAS inhibition (such as ONTARGET and ALTITUDE). Is it still a viable option????

The ADPKD trials story also reminds us of the value of surrogate markers; intervention such as mTOR antagonists and VAPTANS (TOLVAPTAN) reduce cyst size and their expansion...BUT...hardly affect kidney function....!!!! surrogates...surrogates...surrogates....are NO substitutes for HARD ENDPOINTS.

Finally, manipulating key intracellular mediators such as cAMP (Tolvaptan), mTOR (Sirolimus and everolimus) or even key mediators such as the RAA system may do more harm than good!

So far the lessons of clinical translation in ADPKD:

What works in rats and mice doesnt always translate safely and effectively into humans...!!!

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

Anyone in the world

That eGFR is NOT a measure of KIDNEY FUNCTION but instead a CALCULATION/DERIVATION reflecting serum creatinine levels!?

In this month, KI (April 2013): Turin and colleagues from Alberta in Canada show data suggesting that changes in eGFR over time; declining and increasing are associated with increased were independently associated with mortality. http://www.ncbi.nlm.nih.gov/pubmed/23344477

Abstract: Using a community-based cohort we studied the association between changes in the estimated glomerular filtration rate (eGFR) over time and the risk of all-cause mortality. We identified 529,312 adults who had at least three outpatient eGFR measurements over a 4-year period from a provincial laboratory repository in Alberta, Canada. Two indices of change in eGFR were evaluated: the absolute annual rate of change (in ml/min per 1.73 m(2) per year) and the annual percentage change (percent/year). The adjusted mortality risk associated with each category of change in eGFR was assessed, using stable eGFR (no change) as the reference. Over a median follow-up of 2.5 years there were 32,372 deaths. Compared to the reference participants, those with the greatest absolute annual decline less than or equal to 5 ml/min per 1.73 m(2) per year had significantly increased mortality (hazard ratio of 1.52) adjusted for covariates and kidney function at baseline (last eGFR measurement). Participants with the greatest increase in eGFR of 5 ml/min per 1.73 m(2) per year or more also had significantly increased mortality (adjusted hazard ratio of 2.20). A similar pattern was found when change in eGFR was quantified as an annual percentage change. Thus, both declining and increasing eGFR were independently associated with mortality and underscore the importance of identifying change in eGFR over time to improve mortality risk prediction.

OLA BLOG COMMENT:

Throughout the discussion the authors refer to changes in "kidney function" relying on changes with time in estimated GFR (eGFR)!!!!!

When will nephrologists remember that changes in eGFR DO NOT equate solely to changes in RENAL FUNCTION....???

Instead, they equate to changes in serum creratinine levels.

When will Nephrologists remember that changes in serum CREATININE levels can be due to a number of non-renal factors??? including:

Dietary intake

Muscle mass and Creatinine metabolism

When will Nephrologists relaise that a fall in creatinine, especially in the elderly, is a reflection of sarcopenia; itself associated with increased risk of death!

So rather than argue that a rising creatinine is bad news, they should have argued, or at least mentioned..., that a falling serum creatinine is bad news; WASTING and SARCOPENIA in the elderly increases risk of MORTALITY!

So the observation under discussion reminds me of the REVERSE EPIDEMIOLOGY observed in renal ESRD patients; serum: low potassium, low creatinine, low phosphorus are all predicotrs of higher mortality....due to MALNUTRITION and WASTING, so does low serum albumin!

The authors have merely extended these observation to an observed cohort showing that falling/declining serum creatinine levels are equally associated with higher mortality in people with CKD, mostly elderly.

Similar misrepresentations of eGFR are contaminating our literature.

One such example:

eGFR and progression of Alzeihmer's disease (AD); nothing to do with eGFR but instead all to do with falling LEAN BODY MASS (LBM)!

"....Individuals with AD demonstrated a paradoxical finding in which lower baseline MDRD eGFR (HIGHER SERUM CREATININE) was associated with less cognitive decline and brain atrophy, a phenomenon not observed in non-AD controls.Those with lower eGFR had HIGHER LBM; in other words, less wasted and sarcopenic...."

http://www.ncbi.nlm.nih.gov/pubmed/21098656

Therefore accounting for LEAN BODY MASS would significantly mitigate the misinterpretation of such observations including that relating to mortality with higher eGFR.

It is high time that Nephrologists remember and dont forget that eGFR DOES NOT EQUATE TO MEASURED GFR!

and

That eGFR is an unsuitable tool to measure renal function in those with declining muscle mass!

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

Anyone in the world

A debate has been raging for years between those who advocate health through public and governmental policies and those who feel the public should be informed and left to choose what is best for its health.

A number of reminders have recently highlighted such dilemmas.

In a March issue of the NEJM, Kotchen and colleagues remind the readers of the issue of Dietary Salt in health and diseasehttp://www.ncbi.nlm.nih.gov/pubmed/23534562

They put forward an extremely balanced review of the arguments for dietary salt restrictions and the worldwide recommendations to reduce dietary salt intake (sodium chloride intake to around 5g/day). They also put forward the reservations some have about translating science into public policies as well as the potential risks associated with overzealous implementation; a J-shapes curve may for instance characterize the relationship between salt consumption and cardiovascular morbidity and mortaility.

http://www.ncbi.nlm.nih.gov/pubmed/22639013

http://www.ncbi.nlm.nih.gov/pubmed/22068711

It is also notable that in spite of worldwide salt restriction recommendations and public policies, that the public has not followed as shown by data from the US showing little change over the last decade in salt consumption; remaining around 8.5g of sodium chloride/day!? This is to a large extent the reflection of the very high salt content of processed and packaged food as well as the quality of fast food provided by restaurants and fast food chains...cheap food is salty! http://www.ncbi.nlm.nih.gov/pubmed/20577156

This debate and limitations of public health policies brought into focus the current difficulties the mayor of New York City (Michael Bloomberg) is facoing with his Soda Ban; the ban on serving in NY city sugary beverages in containers larger than 16 ounces (475ml). This initiative was successfully challenged in court as a judge judged it to be..."arbitrary and capricious...". Clearly, Big Soda (industry) won the first round! Mayor Bloomberg is appealing...

Big Soda like Big Tobacco industry before it is fighting back. Big Tobacco (industry) has fought ban on smoking in public places for decades only to loose such a battle in recent years when a growing number of countries have implemented a no smoking policy in public places. Whilst such ban remains subject to scrutiny and its impact on public health difficult to evaluate for years, initial analysis suggest major health benefits in the short and long term: http://www.ncbi.nlm.nih.gov/pubmed/21976052. In the meanwhile Big Tobacco (industry) has moved on to promote smoking in emerging economies where it is rapidly rising, along with the risk of cardiovascular disease!

The questions I really ponder are:

1. Is science directly translatable to public health policies?

2. Are public policies the answer to public health issues?

3. Are public health policies effective?

4. Why is the public so reluctant to implement them?

Ultimately should the Public be Forced, Coerced or Taxed to a better Lifestyle or Informed and Educated to choose for Himself...?

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