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Picture of Meguid El Nahas
by Meguid El Nahas - Friday, 19 October 2012, 11:40 AM
Anyone in the world

BEACON, the Phase III RCT launched by Abbot in 2011 to study the effect of Bardoxolone on the progression of diabetic nephropathy has been terminated by the sponsor due to serious adverse events including increased death rate.

BEACON was launched in mid-2011 and involved 1,600 patients with type 2 diabetes and stage 4 CKD. It built on the apparent, and I stress apparent...(see below), success of BEAM, the phase II study that claimed improved kidney function on those treated with Bardoxolone over a 12 months period. BEACON was designed to assess whether bardoxolone could delay progression to the first event of end-stage renal disease, such as dialysis or death from cardiovascular causes.

Bardoxolone, a drug designed by Reata, activates Nrf2, a protein believed to be a principal regulator of cellular antioxidation and detoxification enzymes, while suppressing NFkB, a primary regulator of inflammatory genes. NFkB is thought to play a major role in the progression of renal inflammation associated with progressive CKD. In fact, many of the putative mediators of CKD progression, such as angiotensin II and endothelin1, are known activators of NFkB. Inflammation mediated by NFkB is thought to play an important role in the progression of diabetic nephropathy (1).

At the ASN in Denver 2010, the BEAM investigators revealed with great aplomb that Bardoxolone improves kidney function and slows the progression of diabetic nephropathy. I remember that I was compelled to stand up and draw the attention of the author/presenter of the data that what he presented is that Bardoxolone decreases serum creatinine acutely, within weeks, and subsequently increases estimated GFR (eGFR). I stressed to the author that eGFR does NOT equate to measured GFR. He seemded surprised....and the Chair of the session (Drs Agarwal and De Zeeuw) came to his defence...?! It was also noted by Dr Parving that the low level of proteinuria observed in the patients studied made diabetic nephropathy most unlikely at this advanced stage (CKD3) of renal impairment. Also of note, the control group did not progress; most unusual for CKD3 diabetic nephropathy....

In 2011, the prestigious NEJM published the results of BEAM study and showed all its limitations. Mainly, that this agent primarily lowered serum creatinine and was associated with weight loss. But also may have a potential toxic effect on renal tubules with changes in serum magnesium, uric acid and phosphorus denoting a potential tubular effect/toxicity.  The conclusion, and excitement that followed that publication...., once more revealed the influence of Pharma on Nephrology, Nephrologists and how the latter are not capable of critical thinking. Phase III was planned, BEACON was launched with the same limitations: USING eGFR TO ESTIMATE PROGRESSION OF DIABETIC KIDNEY DISEASE....WHEN ANY NEPHROLOGIST WORTH ITS SALT WOULD KNOW THAT eGFR DOES NOT EQUATE WITH MEASURED GFR!!!!

Once more, most Nephrologists enthusiastically embraced the BEAM findings, thus relinquishing critical thinking and even plain thinking that changes in serum creatinine could have been affected by:

1. Weight loss (observed), 2. Changes in tubular handling of creatinine, along with uric acid and magnesium (Observed) as well as 3. Loss of appetite and decreased protein intake. 

Some didnt, as shown by their sharp and perceptive letters to the NEJM Editor (3)!

The story of BEAM and BEACON should once and for all draw our attention to a number of facts related to RCT in Nephrology:

1. The power of the Pharmaceutical Industry that dictates to clinical investigators the conduct and often interpretation of clinical trials and their results (interestingly enough, I am currently reading "Bad Pharma: How Drug companies mislead doctors and harm patients" the book just published by Ben Goldacre that makes precisely that point...[4]).

2. The all too enthusiastic willingness of Clinical Investigators to embrace positive results related to new interventions without dwelling on their potential side effects and harm...

3. The all too enthusiastic and non-critical acceptance of published data by the nephrology community, specially when featuring in a prestigious medical journal.

4. That prestigious medical journals have reviewers who may be less than critical in their appraisal of publications?! 

5. That eGFR is USELESS if we want to ascertain the effect of an intervention on the progression of CKD; it is a poor surrogate endpoint as is serum creatinine. The true hard endpoint to study progression of CKD is MEASURED GFR!

Finally, I recommend to all nephrologists to read Bad Pharma! It is an eye opener...

Like many examples quoted in this book....Reata/Abbot took a potentially dangerous drug through phases 1 and 2 clinical research overlooking its harm...and focusing on its potential commercial and financial benefits....doctors went along...?!

It is high time, that we as nephrologists and as a medical profession become more critical of published data and sponsored research. 

It is high time we remember our Hippocratic Oath: FIRST DO NO HARM!

References:

 

1. Schmid HBoucherot AYasuda YHenger ABrunner BEichinger FNitsche AKiss EBleich MGröne HJNelson PJSchlöndorff DCohen CDKretzler MEuropean Renal cDNA Bank (ERCB) Consortium.Diabetes. Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathyDiabetes 2006 Nov;55(11):2993-3003.
 

 

 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Wednesday, 17 October 2012, 10:13 AM
Anyone in the world

 

Read this weeks Lancet 13th of October 2012:
WARDS ROUNDS: WHAT GOES AROUND COMES AROUND!
The Royal College of Physicians (RCP) and the Royal College of Nursing (RCN) have released on the 4th of October 2012, a guidance entitled Ward Rounds in Medicine. 
http://www.rcplondon.ac.uk/resources/ward-rounds-medicine-principles-best-practice. 
 
In it they stress the importance of ward rounds and regular as well as genuine patient-doctor contact.
 
The importance of communication between doctors and patients is highlighted by the growing number of patients' complaints to the General Medical Council (GMC) about poor or failure to communicate and lack of respect!
It has been said that "....our conversations with patients are a critical part of the bedside care..." to take time and sit by teh patient's bedsite can make all the difference to him and his families.
 
I remember with nostalgia my social ward rounds; when I used to go round the patients in the evening before going home and chatted to them and their families...these were the good old days!
 
Nowadays, doctors are too busy....we keep hearing! Too busy for what I ask? Talking to patients....????? Instead doctors and nurses spend hours talking to computers and entering endless data from their doctors/nurses stations!?
 
So...back to Ward Rounds in Medicine. The document suggests the use of checklists for ward rounds from preparation, to team, to medical review, to decision making, delegation, etc....but it also reminds doctors and nurses that they need to focus on communications: "Pause: confirm team understanding...", "Pause: confirm patient understanding....". We all too often mumble a few jargonic expression from the end of the patient's bed, leave the patient bewildered..."what did the doctor say...???" and move on to repeat this performance at the next bed....
 
It is time we teach younger doctors the art of Ward Rounds...an art lost along with that of history taking...or physical examination....
 
After all, in this day and age we are good at talking to computers...why bother talking to patients...they also have the internet to chat and socialise with....!!!!! Thats perhaps one sad way of looking at it....NOT MINE!
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world

There are 2 great reads in a recent BMJ - charting the  journeys of 2 different patients through end stage kidney disease. Nicholas Evans author of The Horse Whisperer describes how both he and his wife developed AKI whilst on holiday secondary to mushroom poisoning with Cortinarius speciosissimus. Neither recovered and Evans gives an eloquent account of a gruelling life on dialysis - things such as the devastating impact of intradialytic hypotension and his naive belief that dialysis would give him more time to write - only to realise that he was simply too exhausted and disoriented to work either during dialysis or afterwards. Evans seemed to have had great care throughout and all ended happily as his daughter successfully donated a kidney to him. He movingly describes the transition from reluctance to accepting a kidney from his child to grateful acceptance.

Renata Carey is a diabetic lady in her 70s who describes a journey that all caregivers and patients will recognise. Much of the care she received at the Royal free Hospital, London was 'mostly excellent' but the sheer drudge and loneliness of dialysis takes its' toll.  She described how nobody warned her that she would become anuric and how upsetting this was. Furthermore she reminds us how our best intentions as caregivers can seem simply seem ghastly to patients. For example 'self care' for dialysis patients, which is very much in vogue in the UK, is described by Carey as something foistered upon her - when all she wants is for somebody else to do the caring for her - and quite frankly who can blame her?

Whats striking is that what matters most to her on the dialysis unit is for is for staff to show " kindness, thought and imagination."  Yet within the factory-like setting of the dialysis unit this is in short supply. Facing time-pressures, we get caught up in number watching - obsessing about about lab tests that mean little to patients and in many cases have only a marginal impact on  quality of life. Most of all these journeys remind us how that essential element of great healthcare - humanity - is fiendishly hard to deliver and frequently elusive....All staff involved in the care of dialysis patients will learn much from reading and reflecting on these journeys....

1. Kidney dialysis--the need for humanity. Carey R, Harber M. BMJ. 2012 Jul 19;345:e4492. 

2. Irreversible renal damage from accidental mushroom poisoning. Evans N, Hamilton A, Bello-Villalba MJ, Bingham C.BMJ. 2012 Aug 10;345:e5262.

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

There is a great review of the Iranian model of living kidney transplantation by Mitra Mahdavi-Mazdeh in this months Kidney International. The process of unrelated transplantation is described in some detail but in essence involves a kind of regulated negotiation between donor and recipient at a patient 'kidney-foundation' clinic. Once a patient has been deemed suitable for a transplant the foundation provides a space for a negotiation between donor and recipient - this is a pure financial transaction and as in all such transactions there is hard negotiation over the price. Once the transplant goes ahead the government provides 1 years of medical insurance plus $900 USD to the donor. The recipient is covered for life for the cost of immunosuppressive drugs (a benefit not yet afforded to Medicare patients in the USA). There is no doubt that the donors were poorer and of lower socio-economic status than the recipients. Whilst many may feel uneasy about the ethics of the process its worth considering the following:

i) The program has delivered transplantation successfully to huge numbers of patients who previously would have been condemned to a life on dialysis. Without such a system patients would have quite simply died - there was no deceased donor program in Iran for many years. For those of us sitting in the luxury of our ivory towers its easy to get queasy about ethics.. for patients such transactions are quite literally a matter of life and death. The Iranian government is currently piloting a 'fixed-price' model which may perhaps remove some of the stress related to the transaction.

ii) the success of the live transplant program has been absolutely instrumental in developing a blossoming brain death donation (BDD) program - whilst change in legislation was the catalyst for the growth in the BDD program,  without the development of a successful live program with associated clinical expertise and infrastructure it is unlikely that the political establishment would have supported the initiation of BDD program.

iii) Disappointingly the live-related transplantation rate has remained relatively low and static over the last 10 years - perhaps confirming the impression that wealthier families would rather buy kidneys form poorer donors rather than 'gift' a kidney to a family member

iv) the Iranian experience is not only important to Iran but crucially provides a template to develop an active, high quality program in other emerging countries as well as in Islamic societies where kidney transplantation rates are often disappointingly low. What works in the USA and Europe often doesn't work in Africa, Asia or the Middle East. What Professor Mahdavi-Mazdeh has shown is that countries need to think outside the 'western paradigm' of transplantation and develop their own 'local' solutions to transplantation. 

v) Critical to the success of the Iranian program is the way clinical leaders engaged with politicians, religious organisations and wider society - irrespective of where we live this is something we can all learn from

vi) In an accompanying commentary, Francis Delmonico from Harvard University, Boston rightly points out that there is no long term outcome data on the donors from Iran.  Furthermore Delmonico states that donors tend to be 'poor, hapless, jobless and largely destitute' and argues that 'the exploitation of the poor that has enabled most Iranian kidney transplantations'. For Delmonico the fundamental unethical aspect of the process is the 'victimisation of the poor'. 

This may well be true and the concerns raised are valid but we need to remember that in many societies ESRD is an immediate death sentence. There is a more than a hint of 'academic imperialism' here - Delmonico does not have to look far to find evidence of 'victimisation of the poor' in healthcare - an astonishing 16% of Americans have no health insurance with catastrophic consequences - public health experts from Harvard estimating that this results in nearly 45,000 extra deaths per year. Now that really is 'fundamentally unethical'......

 

References

 

1. The Iranian model of living renal transplantation. Mahdavi-Mazdeh M. Kidney Int 82: 627-634; advance online publication, June 6, 2012; doi:10.1038/ki.2012.219

2. The Alternative Iranian model of living renal transplantation. Francis L Delmonico. Kidney Int 82: 625-626; doi:10.1038/ki.2012.247

3. Health Insurance and Mortality in US Adults. Wilper Ap et al. Am J Public Health. 2009 December; 99(12): 2289–2295.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Thursday, 6 September 2012, 2:16 PM
Anyone in the world

An interesting article in the BMJ by Prof Yudkin and colleagues in London is entitled:

"The Idolatry of Surroagtes"

http://www.ncbi.nlm.nih.gov/pubmed/22205706

In this article, the authors raise serious and justified concern about the use of surrogate markers as substitutes for hard endpoints in clinical research and trials. They quote a number of examples whereby reduction in surrogate markers are not associated with changes or diverge from expected hard endpoints. 

They comment specifically on albuminuria and raise concern about its disconnect with hard renal and cardiovascular endpoints.

This concern is supported by data showing that a reduction of albuminuria can be associated with imporved renal function (RENAAL), unchanged renal function (ACCORD study) or worse stilll worsening of renal function (ONTARGET). Clearly, reduction of albuminuria can also be misleading if considered a CV endpoint as the ROADMAP study showed  that prevention/reduction of Microalbuminuria with Olmesartan in DM was in fact associated with increased CVD morbidity. 

So lets stop being obssessed with reduction of proteinuria in CKD and focus of the true hard endpoints of death and ESRD. 

I despair when I hear senior nephrologists argue that reduction of proteinuria should take precedent over declining kidney function or starting ESRD....thus continuing to poison their patients with ACE inhibitors and ARBs and accelerating the time to ESRD in the name of reducing proteinuria and preventing CVD....!!!!

Care should be taken in clinical trials, but also in daily practice, not to treat the markers/symptoms of disease on the assumption that we treat the underlying disease or its cause.

This explains why the FDA rightly continues to reject albuminuria as a surrogate marker for ESRD, or even the progression of CKD. The FDA has also recently become more stringent in its requirements that drugs under development are shown to affect favourably hard endpoints at the risk of prolonging the cost and duration of drug development. Better be safe than sorry later...

For the Pharmaceutical industry to steamroll drug developments and marketing using surrogate markers of mortality, CVD, CKD progression or ESRD as albuminuria is unacceptable and potentially dangerous. Even serum creatinine, and the asociated eGFR, should be looked upon with caution when we investigate an intervention aimed at slowing the progression of CKD, delaying ESRD or preventing Death. Serum creatinine is a marker of a number of confounders including protein intake, metabolism, muscle mass and tubular secretion of creatinine; it is NOT a hard enpoint for progression of CKD. For that, MEASURED GFR is the gold standard!

http://www.ncbi.nlm.nih.gov/pubmed/22393413

It is high time the nephrological community discern soft surrogate markers from hard endpoints.

Nephrologists need to realise that hard end points are essential for the practice of true patients centered medicine.

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Tuesday, 4 September 2012, 7:58 AM
Anyone in the world

In this week (September 1-7, 2012: http://www.ncbi.nlm.nih.gov/pubmed/22717317) issue of the Lancet, Tonelli and colleagues from Alberta explored whether CKD was a coronary artery disease (CAD) risk equivalent. Risk equivalent would imply that the 10 year CAD risk associated with CKD (eGFR<60) is 20% similar to that affecting sufferers of myocardial infarction. They studied a local cohort of 1,268,029 individual over a 4-5 year period.

They concluded that: "Our findings suggest that chronic kidney disease could be added to the list of criteria defining people at highest risk of future coronary events"

However, reading the paper I come to different conclusions:

1. The rate of myocardial infarction (the primary end point) was higher in people with previous myocardial infarction than in those with CKD.

2. It is true than unadjusted risk rate in CKD was higher than that of people with diabetes (illustrated in the Figure, for maximal impact....).

However,

3. When risk is adjusted for age (older in CKD compared to those with DM) as well as CVD co-morbidities the adjusted risk no longer exceeds that of DM. In other words, the increased risk associated with CKD was to a large extent the reflection of older AGE but also of CV CO-MORBIDITIES associated with older age...

So, as stated on numerous previous occasions on OLA, CKD is a CVD risk marker for the simple reason that:

a. Individuals with CKD and a eGFR<60 are older and have been exposed in their lifetime to CVD risks such as hypertension, obesity/DM, and dyslipidemia. Not to mention the presence of anemia which in a previous study seemd to explain most of the CVD risk associated with CKD (Vlagopoulos et al, 2005). None of these confounders has been explored in the Tonelli analysis.

b. Individuals with CKD have underlying overt or subclinical CVD including CAD, thus making them at obvious CVD risk as they already suffer from CVD....(Park et al, 2012: http://www.ncbi.nlm.nih.gov/pubmed/22935481).

Also, as previously shown in a number of studies reviewed by Chang and Kramer in 2011 (http://www.ncbi.nlm.nih.gov/pubmed/21811078), adding eGFR or albuminuria to standard CVD risk scores, such as the Framingham Risk Score, adds little to the predictive value of established CVD scoring system.

Had Tonelli and colleagues checked conventional CVD risk factors such as Hypertension, Smoking and dyslipidemia in the community studied, they would have found that CKD patients with eGFR <60 or worse still <45 have been exposed to most of these confounders or CVD risk...and that CKD merely reflects in th eelderly such lifetime exposure, leading to CVD and consequently to CKD!

Finally, the authors and the accompanying review make the point that CKD patients should therefore be put on statins in view of their high CVD risk. This is true intuitively, but unproven clinically as the SHARP study they both refer to FAILED to show any benefit of statin + Ezetemibe treatment in CKD as far as prevention of CAD or reduction of overall mortality. So there is NO EVIDENCE that statins reduce the coronary events risk the authors are focusing on in CKD or even in those with ESRD with DM (4D study) (http://www.ncbi.nlm.nih.gov/pubmed/19332456).

Altogether, it is high time that the Nephrology community comes to realise that CKD is a CVD risk equivalent because CKD = CVD in the ageing general population where age, hypertension, obesity, DM, dyslipidemia and smoking are prevalent and individuals often have overt (but undiagnosed) or subclinical (not tested for...) CVD. Of note, the Baltimore Longitudinal Study of Ageing showed many years ago that age related decline in kidney function was prominent in those with co-morbidities.

Chicken and Egg situation where the chicken is CVD and th eegg is CKD...!!!

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Friday, 31 August 2012, 7:08 AM
Anyone in the world

In this month (August 2012) Ann Int Med. the US Preventive Services Taks Force concluded that it was NOT justifiable to screen the general population (asymptomatic individuals) for CKD.

 

Population

Asymptomatic adults without diagnosed chronic kidney disease (CKD)

Recommendation

No recommendation.

Grade: I (Insufficient Evidence)

Risk Assessment

There is no generally accepted risk assessment tool for CKD or risk for complications of CKD. Diabetes and hypertension are well-established risk factors with strong links to CKD. Other risk factors for CKD include older age, cardiovascular disease, obesity, and family history.

Screening Tests

While there is insufficient evidence to recommend routine screening, the tests often suggested for screening that are feasible in primary care include testing the urine for protein (microalbuminuria or macroalbuminuria) and testing the blood for serum creatinine to estimate glomerular filtration rate.

Balance of Harms and Benefits

The USPSTF could not determine the balance between the benefits and harms of screening for CKD in asymptomatic adults.

Other Relevant USPSTF Recommendations

The USPSTF has made recommendations on screening for diabetes, hypertension, and obesity, as well as aspirin use for the prevention of cardiovascular disease. These recommendations are available at www.uspreventiveservicestaskforce.org.

For a summary of the evidence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents, please go to www.uspreventiveservicestaskforce.org. 

This should put a temporary end to the question as to whether the general asymptomatic adult population should be screened for CKD.

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Wednesday, 22 August 2012, 9:26 AM
Anyone in the world

 

Professor Rashad Barsoum wrote:
 
The question of renal transplantation in patients with a history of schistosomiasis infections raises a number of issues:

a) Surgical risk; b) pharmacokinetics and potential toxicity of immunosuppressive agents; c) short- and long-term outcomes; d) recurrence of the original disease; e) Reinfection.
In urinary schistosomiasis, the surgical risk is related to the presence of infection, motor abnormalities of the bladder, outflow or upstream obstruction. All these issues are amenable to adequate management, which may be simple or highly complicated. Pre-transplant urological procedures may be necessary for ensuring adequate bladder capacity and function. In some cases, persistent infection may require bilateral nephrectomy.
In hepatosplenic schistosomiasis the surgical risk is assessed by the usual CHILD criteria, which are quite valid in schistosomiasis. Please mind the frequent association with HCV infection, which has its own constraints with regards to transplantation. The presence of portal hypertension with ascites and porto-systemic shunts should be seen as a contraindication to transplantation.
A thesis presented to Alexandria University has evaluated the metabolism of immunosuppressive agents in patients with hepato-intestinal transplantation. It concludes that if the patient is fit for surgery, the liver function should be good enough not to impose a significant perturbation to the pharmacokinetics of commonly used immunosuppressive agents. We have not been able to show that the toxicity of antiproliferative agents, PSI’s or CNI’s is increased in patients with hepatosplenic schistosomiasis with fair liver functions that permit surgery.
The short-term outcomes of transplantation in patients with schistosomiasis are generally non-inferior to those without schistosomiasis, so long as the pre-operative criteria are favorable as described above. In one study, the incidence of ureteric leaks was relatively higher in patients with urinary schistosomiasis. Some surgeons prefer uretero-ureteric to uretero-vesical anastomosis to avoid cutting through the fibrotic bladder wall. I am unaware of any studies that compare this approach to standard uretero-vesical anastomosis.
In the few reports that addressed long-term outcomes, there have not been any significant alterations in patient or graft survival at 5 years. But all patients included were well selected according to the above criteria.
Recurrence of schistosomal nephropathy has been reported in Brazil, not in Egypt. I presume that adequate pre-transplant exclusion of active infection should obviate this remote possibility.
Re-infection has been addressed in a nice paper from Mansoura. Since many recipients eventually resume their social habits of contact with contaminated water, their chances of getting re-infected are obviously high, particularly with their immunosuppression. In the mentioned study, re-infection occurred in a higher proportion of patients receiving kidney transplants compared the norms in the same community.
So, the key for a good transplant outcome is good selection, which brings us back to the second and third paragraphs of this comment.
Rashad Barsoum

 

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

In this wek's NEJM, an article by Olesen and colleagues from Denmark shows that CKD is associated with increased risk of stroke and thromboembolism in patients withatrial fibrillation (AF); hazard ration in CKD ~2, and HR in ESRD ~3 (compared to general, non CKD, population).The data was derived from Danish National Registries and from an observational cohort of around 4,000 patients with CKD (3587 non-ESRD CKD) and 901 with ESRD. http://www.ncbi.nlm.nih.gov/pubmed/22894575

They also show that warfarin therapy is associated with significantly decreased risk. But there was a 33% increased risk of bleeding with warfarin therapy in CKD patients compared to those without CKD. Aspirin was not associated with decreased risk.

This analysis supports a recently published meta-analysis showing the beneficial effect of warfarin anticoagulation in incident AF patients: http://www.ncbi.nlm.nih.gov/pubmed/22450212. In this anlysis, there was a significant increase in the annual incidence of stroke with progressively increasing CHADS(2) (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores.

The implications of the Olesen et al study would be to recommend warfarin therapy in patients with AF with CKD/ESRD. This would be all the more justified in view of the fact that most of the ESRD patients would have a CHADS score>2; old, hypertensive, diabetic with underlying CVD!

What the authors dont mention is the risks associated with warfarin therapy in ESRD.

There is growing evidence and concern that warfarin therapy is potentially harmful in this population due to the impact of warfarin on vascular calcifications as well as calciphylaxis. There is also evidence to link warfarin use and increased mortality in this population. The impact of warfarin on vascular calcifications has been l;inked to its inhibitory effect on vitamin K synthesis as well as that of other proteins. Apart from clotting factors, vitamin K-dependent proteins include regulatory proteins like protein C, protein S, protein Z, osteocalcin, growth arrest-specific gene 6 protein, and matrix Gla protein (MGP). MGP is a known natural inhibitor of vascular calcifications present in vascular walls and strongly inhibited by treatment with warfarin.

In addition to bleeding and vascular calcifications, other risks have been associated with the use of warfarin, including an increased susceptibility to fractures caused by a reduction in the levels of vitamin K dependent carboxylated enzymes, matrix Gla-protein (MGP) and bone Gla-protein or osteocalcin (BGP).

Consequently, anticoagulant therapy in patients with with CKD/ESRD and AF requires careful evaluation because its benefits i.e. prevention of thromboembolism, must be greater than the risk of bleeding. Patients at higher risk of thrombosis are evaluated through specific scores, such as the CHADS(2), coupled with scoring systems for assessing bleeding risks, such as the HAS-BLED score.

Caution should therefore be exerted in using Warfarin in patients with AF and advanced CKD.

Alternate therapies may have to be considered with a more favourable RISK:BENEFIT profile. Newer anticoagulants such as dabigatran and rivaroxaban offer promise as future therapeutic options in such cases.

Drugs including statins and vitamin K are currently under study as therapies to prevent or treat warfarin-associated calcification. A large EU study of the effect of vitamin K1 (precursor of K2) in HD patients is underway.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Friday, 17 August 2012, 11:31 AM
Anyone in the world

 

This is the real problem of CKD....Ageing and the associated Co-Morbidities!
 
Age-associated increased Co-Morbidities impacts on kidney function from the age of 45 onward!
 
Consequently, CKD increases with age and represents the majority of those detected within communities with impaired kidney function. 
 
In order to reduce the incidence of CKD, attention (Prevention & Detection) should focus on predisposing NCDs:
 
HYPERTENSION, DIABETES AND CVD!
 
Data from the National Health Interview Survey, 1999–2000 and 2009–2010
 
• Between 1999–2000 and 2009–2010, the percentage of adults aged 45–64 and 65 and over with two or more of nine selected chronic conditions 
increased for both men and women, all racial and ethnic groups examined, and most income groups.
 
• During the 10-year period, 
the percentage of adults aged 65 and over with both hypertension and diabetes increased from 9% to 15%; 
prevalence of hypertension and heart disease increased from 18% to 21%;
and prevalence of hypertension and cancer increased from 8% to 11%. 
 
• The percentage of adults aged 45–64 with two or more of nine selected chronic conditions who did not receive or delayed needed medical care due to cost increased from 17% to 23%, and the percentage who did not receive needed prescription drugs due to cost increased from 14% to 22%.
 
http://www.cdc.gov/nchs/data/databriefs/db100.htm
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