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by Meguid El Nahas - Friday, 2 May 2014, 5:19 PM
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It came to my attention over the years that medical education in some emerging countries is based on endless learning by rote (memorising knowledge based on repetition) without much in the way of focused or reflective learning.

Seniors educators seem to use these techniques to maintain some form of ascendency over juniors and restrict their progress. Whilst this sounds pernicious, it seems quite prevalent. Juniors learn endless list of differential diagnosis, never long enough for their seniors, who always find yet another rare or esoteric disease to trip the junior and show his supremacy. This is also the case in exams where examiners seem to take a malicious pleasure of tripping young doctors by asking them the most obtruse and obscure of medical questions... 

This attitude and deference to seniority seems in the long run to hamper the intellectual development of younger doctors and keep them in a subserviant state of dependency on the unreachable heights of the "Professor" encyclopedic...but really useless....knowledge!

This also translates in overall poor medical care, as those privy to such encyclopedic knowledge acquire it through a bookish attitude to learning rathern than an experiential one based on rich and diverse clinical practice; a huge dichotomy emerges between the exhalted knowledge of these senior doctors and their appalling medical practices...

The juniors, on the other hand, remain in the land of fear of authority, unable to challenge their seniors...and unable to acquire the sound and practical knowledge they crave. Consequently, they are also in a medical no man land where they struggle to find sound clinical guidance and advice.

To please their seniors and gain their approval and promotion, they follow the lead of "impression by rarity..." raising the most unusual and improbable diagnoses to deal with common diseases; so a straightforward UTI raises the possibility of a dysmorphic dysplasia of the bladder epithelium rather than just poor hygiene and faecal contamination of the urinary tract! Or, angina in a older patient with diabetes mellitus raised the spectrum of aneurysmal destruction of the coronary arteries by polyarteritis nodosa....and son on!

What can be done to refocus the minds of new generations of younger doctors subject to this distorted way of thinking?

1. Ignore the seniors as they will not change; they have a vested interest in this pernicious system; it serves them well...

2. For the juniors to make the most of the world of the internet to find alternative methods of educating themselves.

3. Rely on peer support.

4. Rely on network learning and use the amazing range of learning media through the internet to break free from the shackles of seniors who want to keep them enslaved to their whim...

Even then...seniors have ways to keep them at their mercy..."Unless you do as I will not get your higher degree...", "unless you do as I say you will not be promoted..." 

Sad but true...this is the state of continuing medical education in many countries...


[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Arif Khwaja - Friday, 2 May 2014, 9:10 AM
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In the last few weeks I've received 2 contrasting emails from the UK Renal Association (RA) and the International Society of Nephrology both concerning the appointments of people to various positions in each respective society. The RA approach is very simple - any member can stand for any position and is elected by a simple electronic and postal ballot. In other words one member one vote and all the key positions are usually elected. 

In contrast the process for the selection of the president elect of the ISN seems much more opaque. I can nominate somebody, but the nominations are scrutinised by the 'nominations committee' to ensure that the candidate fits in with the 'ISN mission, mindset and spirit.' After that the process to me as an ordinary member isnt clear - but as far as I can tell a shortlist of screened candidates are then voted on in a secret ballot of the ISN council - I maybe wrong on the precise mechanics here but I know one thing is clear - members of the ISN arent able to directly elect the president of the ISN on the basis of one member one vote.

Does any of this really matter? After all the ISN is a great organisation and I'm a proud member of it. For a small fee I get 2 excellent journals ( Kidney International and the brilliant Nature Nephrology Reviews) as well as access to a wealth of educational initiatives and meetings. As an example the Sister Renal Centre and the fellowship programs have been fantastic initiatives in transforming care and developing relationships around the world. I am particularly proud of of our own relationship in Sheffield with Sister Renal Centres in Bosnia and Egypt.

However going back to the process of electing the president of the ISN a few things are clear... if any member wants to change the 'mission, mindset and spirit' of the ISN they would presumably be unable to get past the nominations committee. The contrast with the RA is striking... members stand for various positions with a short statement of their manifesto i.e. what they would like to do. The membership then votes for people on the basis of their positions and whoever gets the most votes assumes the position. Its a great way of ensuring the the leadership of a society reflects the beliefs and wishes of the membership.

When I go to WCN meetings I am always struck by the huge number of people attending from all over the world - a huge mix of nationalities and ethnicities that presumably in part reflects the ISNs very diverse, international membership. Yet a quick look the 22 presidents of the ISN paints a completely different picture: 20 out the 22 presidents have been from Europe, USA and Australia.  The remaining 2 were from Japan and Venezuela, both as far as I can tell had worked in the USA. There has never been a black or brown president. It is amazing that a society that is supposed to represent the international nephrology voice has never had a president from Africa, the Middle East, India or China. 

Does this matter when the presidents have all clearly been people of outstanding calibre? Well yes I think it does matter - societies need to reflect their memberships and for societies to thrive they need to be actively evolving their 'mission, mindset and spirit' to meet the needs of their membership but more importantly the global needs of patients with kidney disease. Its for this reason I hope that one day we will have a president of the ISN who hasn't trained in an academic centre of excellence in North America, Europe or Australasia but somebody who has experienced a completely different clinical environment and who can thereby develop and evolve the ISN further. Diversity matters - not as a sop to political correctness - but as a way of hearing different voices and perspectives and so strenghtening and enriching organisations.

The Athenians first established a democratic process around 2500 years ago and generally the concept has been seen as pretty successful. In the 21st century maybe the ISN should start to look again at the way it chooses its' president.....

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

Prof Macaulay Onuigbo wrote:

Microalbuminuria in current nephrology literature revisited

There is significant evidence in the literature of temporal disassociations between measured kidney function and measured albumin creatinine ratios (ACR) in studied diabetic and non-diabetic CKD patients:

i. Tsalamandris et al. reported that of 40 patients with diabetes, followed over a period of 8-14 years, 15 developed progressive increase in albumin excretion rate (AER) with no decline in GFR, 13 had progressive increase in AER in association with decreasing GFR, and 12 (8 type 2) had decreasing GFR values without a significant increase in AER [1].

ii. In the DCCT/EDIC study, an extended median 13-year follow up of1441 study participants also documented regression to normoalbuminuria after more than a decade of persistent microalbuminuria, mostly without RAAS inhibitor use, and generally in the setting of excellent control of glycemia and blood pressure [2].

iii. In the ONTARGET trial, despite superior proteinuria reduction by combination RAAS blockade with an ACEI and an ARB, the combination group still fared worse than the monotherapy groups with regards to renal outcomes [3].

iv. Our experiences in the last ten years at the Mayo Clinic Health System, Eau Claire, in Northwestern Wisconsin, USA, have demonstrated similar patterns of variability of measured proteinuria by urinary albumin creatinine ratios among type II diabetic CKD patients, on and off the influence of concomitant angiotensin blockade [4-6]. Moreover, while we observed a tendency to increased proteinuria in our CKD patients following discontinuation of ACE inhibitors and/or ARBs, this was often in the face of improved kidney function [4-6].

v. El Nahas et al. from Sheffield, the United Kingdom, who reported on the results of discontinuation of ACE inhibitors and/or ARBs in 52 older CKD patients (21 females and 31 males, mean age 73 years) with advanced CKD (stages 4 and 5), showed sustained improved kidney function but no change in proteinuria following discontinuation of angiotensin blockade [7]. Baseline urine protein:creatinine ratio (PCR) was 77 ± 20 mg/mmol, and compared to end PCR values of 121.6 ± 33.6 mg/mmol, was not statistically significant [7].

From the foregoing, we have therefore been repeatedly called for more caution in the interpretation of degrees of proteinuria as a definitive and proven renal surrogate, more so when it is used in combination surrogate renal endpoints for study endpoints [8-10]. Indeed, Mann et al, the investigators of the ONTARGET trial, in a post hoc analysis concluded that the ONTARGET data suggest that proteinuria reduction by itself cannot be taken as a definitive marker of improved renal function [11].
We agree with El Nahas on a need to re-evaluate some of the current paradigms of CKD care especially as it relates to albuminuria as a renal surrogate [12]. Again, as El Nahas had acknowledged above, a focus on overt and progressive albuminuria is more apt and appropriate.

1. Tsalamandris C, Allen TJ, Gilbert RE, et al. Progressive decline in renal function in diabetic patients with and without albuminuria. Diabetes 1994; 43: 649-655.pmid:8168641.
2. de Boer IH, Rue TC, Cleary PA; et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med 2011; 171(5): 412-420.
3. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–59.
4. Onuigbo MA, Onuigbo NT. Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients. Int Urol Nephrol 2008; 40:233–9.
5. Onuigbo MA, Onuigbo NT. Late onset azotemia from RAAS blockade in CKD patients with normal renal arteries and no precipitating risk factors. Ren Fail 2008; 30:73–80.
6. Onuigbo MA, Achebe NJ. Late Onset Renal Failure From Angiotensin Blockade (LORFFAB) – The Results of a Mayo Clinic Health System Angiotensin Inhibition Withdrawal Study: A Clarion Call For More Preventative Nephrology, Also Called Renoprevention. In: Macaulay Amechi Chuka Onuigbo, Editor. ACE inhibitors: medical uses, mechanisms of action, potential adverse effects and related topics. Volume 1. New York, NY. NOVA Publishers, 2013: 75-90.
7. Ahmed AK, Kamath NS, El Kossi M, El Nahas AM. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant. 2010 Dec;25(12):3977-82. doi: 10.1093/ndt/gfp511. Epub 2009 Oct 10.
8. Onuigbo MA. Relation between kidney function, proteinuria, and adverse outcomes – A critical look at the application of medical statistics in the Nephrology literature. QJM 2010 Jul; 103(7): 537-8. Epub 2010 Apr 11.
9. Onuigbo M, Onuigbo N. Aliskiren in Type 2 Diabetes and Cardiorenal End Points. N Engl J Med. 2013 Mar 14;368(11):1064-5. doi: 10.1056/NEJMc1300257#SA1. (
10. Onuigbo MA. The Abuse of Renal Surrogates and Combination Renal Endpoints in Nephrology RCTs. In: Macaulay Amechi Chuka Onuigbo, Editor. ACE inhibitors: medical uses, mechanisms of action, potential adverse effects and related topics. Volume 1. New York, NY. NOVA Publishers, 2013: 35-40.
11. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372(9638): 547-553.
12. Onuigbo MA. Angiotensin Blockers and Renoprotection in Diabetic Chronic Kidney Disease is a Failed Paradigm? – A Revisionist View of Renoprotection in Diabetic Chronic Kidney Disease and A Novel Classification Scheme for Renoprotective Agents. In Atta ur Rahman (Editor): eBook “Frontiers in Clinical Drug Research: Diabetes and Obesity, Vol. 1”, 2014, In Print.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Meguid El Nahas - Monday, 14 April 2014, 7:45 AM
Anyone in the world
Kidney Int. 2014 Apr 9. doi: 10.1038/ki.2014.98. [Epub ahead of print]

'Progressive diabetic nephropathy. How useful is microalbuminuria?


The concept of microalbuminuria has been central to the development of clinical practice and research in the area of diabetic kidney disease (DKD). However, in recent times, the value of a paradigm of DKD based solely on microalbuminuria has been questioned. Although both the absolute level and rate of change of microalbuminuria are linked to the development and progression of DKD, microalbuminuria on its own lacks the necessary sensitivity or specificity to accurately predict kidney outcomes for people with diabetes. The development of microalbumiuria can no longer be viewed as a committed and irreversible stage of DKD, as spontaneous remission is now reported as a common occurrence. In addition, the absence of microalbuminuria or its progression to proteinuria does not signify that an individual patient is safe from a progressive decline in glomerular filtration rate (GFR). Furthermore, although reductions in albuminuria within the microalbuminuric range can be linked to a slower GFR decline in observational studies, this relationship has not been robustly demonstrated in intervention studies. Conclusions regarding the kidney health of individuals with diabetes will continue to be flawed if an inappropriate emphasis is placed on the presence or absence of albuminuria or changes in albuminuria within the microalbuminuric range. This has important implications in terms of undermining the value of microalbuminuria as a surrogate renal end point for intervention trials. There is a need to develop broader models of progressive DKD that include novel pathways and risk markers apart from those related to the traditional 'albuminuric pathway' to renal impairment.Kidney International advance online publication, 9 April 2014; doi:10.1038/ki.2014.98.


This is an extremely timely review highlighting convincingly the limitations of using microalbuminurioa in diabetic nephropathy diagnosis, monitoring and management. It highlights that microalbuminuria lacks both sensitivity and specificity to diagnose renal involvement and their progression in people with diabetes mellitus. This is all the more significant in T2DM.

Once more, it is important to remember that microalbuminuria is a marker of a number of inflammatory and atherosclerotic conditions associated with DM.

Also within the kidneys, microalbuminuria should be thought of as the end results of abnormalities and dysfunction at many levels:

1. Glomerular filtration of albumin

But also:

2. Proximal tubular reabsorption of albumin

which can be affected by:

3. Peritubular capillary blood flow/renal perfusion

All these can be transiently and also permanently affeceted in people with DM.

It is high time Nephrologists forget about microalbuminuria and focus on overt and progressive albuminuria (dipstick positive).

It seems to me that the era of obssessive search for, and management of, microalbuminuria is coming to an end. Some of us have argued along these lines for a long time. Otherrs want to expand the search and management of microalbuminuria further beyond people with diabetes to the communtiy as a whoile.

How mislead and misleading they are...!!!

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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A recent paper in the Journal of the American Soceity of Nephrology has linked physical exercise  with a slower rate of eGFR decline in patients with CKD3.


Physical activity may counteract metabolic disturbances that promote the progression of CKD. To address this concept, we performed a longitudinal cohort study of 256 participants in the Seattle Kidney Study, a clinic-based study of CKD. Participants with an estimated GFR (eGFR) of 15-59 ml/min per 1.73 m(2) at baseline were eligible for the study. Physical activity was quantified using the Four-Week Physical Activity History Questionnaire. We used generalized estimating equations to test associations of physical activity with change in eGFR determined by longitudinal measurements of serum cystatin C. Mean baseline eGFR was 42 ml/min per 1.73 m(2). During a median 3.7 years of follow-up, the mean change in eGFRcystatin C was -7.6% per year (interquartile range, -16.8%, 4.9% per year). Participants who reported >150 minutes of physical activity per week had the lowest rate of eGFRcystatin C loss (mean -6.2% per year compared with -9.6% per year among inactive participants). In adjusted analyses, each 60-minute increment in weekly physical activity duration associated with a 0.5% slower decline per year in eGFR (95% confidence interval, 0.02 to 0.98; P=0.04). Results were similar in sensitivity analyses restricted to participants without cardiovascular disease or diabetes, or to participants with moderate/high physical function. After adjustment for eGFR at the time of questionnaire completion, physical activity did not associate with the incidence of ESRD (n=34 events). In summary, higher physical activity levels associated with slower rates of eGFR loss in persons with established CKD.


This is an interesting observation that falls within the usual trap of eGFR calculation and measurement.

The authors used eGFR Cystatin C to estimate changes in GFR, thus equating once more changes in a surrogate marker, in this instance CystatinC, as an indicator of changes in Glomerular Filtration Rate; that wasnt measured!

As with studies relying on eGFR Creatinine (MDRD or CKD-EPI equations), the use of such surrogate markers (serum creatinine or cystatin C) needs to take into considerations the non-GFR confounders associated with such a marker:

So for serum creatinine:

Dietary protein/creatine/creatinine intake

Creatine/creatinine metabolism and muscle mass

Tubular secretion of creatinine

For serum Cystatin C:

Obesity, smoking as well as inflammation have been associated with increased circulating levels of this bioamrker.

Therefore, when considering changes in the calculated eGFR based on these biomarkers, it is essential that the intervention under study doesnt affect the variable in other ways, independently, from changes in GFR.

So for example a low protein diet would improve the eGFR (creatinine) decline rate by decreasing serum creatinine/increasing eGFR through a reduction in dietary protein, changes in creatinine meatbolism as well as the possibility muscle wasting.

Now, in the publications under discussion the biomarker used to measure and calculate eGFR is Cystatin C, thus claiming that improved eGFR Cyst takes place in those undergoing regular physical exercise.

So we have to ask ourselves is Cystatin C affected by exercise through non-GFR pathways?

And the answer is possibly. Cystatin C is know to be raised in chronic inflammation. CKD is known to be associated with chronic inflammation. And...exercise is known to reduce inflammation in CKD patients. In a recent publication in JASN (April 2014), investigators in Leicester (UK) showed that acute exercise induced a systemic anti-inflammatory environment most likely mediated by increased plasma IL-6 levels. Furthermore, they noted that 6 months of regular walking exercise (30 min/d for 5 times/wk) exerted anti-inflammatory effects (reduction in the ratio of plasma IL-6 to IL-10 levels) and a downregulation of T-lymphocyte and monocyte activation.

So once more one has to question whether the changes observed in the under discussion publication are directly related to changes in the rate of progression of CKD OR instead in the rate of progression of inflammatory changes associated with CKD and reflected in the changes in an inflammtory marker namely serum Cystatin C; possibly wrongly assumed in this study to reflect changes in GFR.

Increasingly the literature is overloaded with publications using eGFR as a synonym for measured GFR; this is a grave error and open to considerable misinterpretation whether serum creatinine measurement is used to estimate eGFR or whether it is Cystatin C as in the publication under discussion.

It is high time Nephrologists learn that if they want to study CKD progression they need to measure CKD progression and not rely on dubious and confounded surrogate biomarkers!



[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Meguid El Nahas - Monday, 7 April 2014, 4:20 PM
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An excellent editorial by Steven Rosansky and Richard Glassock review issues related to the estimation of CKD progression in renoprotection drug trials.

The authors examine the currently used parametres of CKD progression:

1. ESRD and Renal Replacement Therapy (RRT)

They note that RRT initiation as a hard point has its limitations in view of trends over the last decade in early initiation of RRT. They also note the non-GFR related alterations in serum creatinine levels including alterations in endogenous creatinine generation due to diet and sarcopenia.

the authors recommend a harder endpoint of fixed eGFR of 15ml/min/1.73m2.

Some would argue that mGFR of 10ml/min/1.73m2 is a more valid endpoint.

2. The decline in eGFR

using the decline in eGFR is fraught by the fact that many patients dont progress or progress in a non-linear fashion. Increasingly nephrologists have come to realise that CKD progression is not invariable with a significant percentage not progressing for long period of time and some progressing in a non-linear fashio whilst some even improving with time. Such non-progression or a non-linear progression RFT would make endpoints based on RFT unpredictable and difficult to interpret in a clinical trial.

They also note that some interventions such as Low protein diet (MDRD study) or ACE inhibition may lead to an initial acceleration of GFR decline before longer term stabilisation/renoprotection.

The FDA recently suggested a 30% decline and a 40% decline in GFR from baseline values as new surrogate end points in intervention studies. This on the assumption that the decline in GFR is linear.  

This would be preferable to the current doubling of serum creatinine (50% decline in GFR).

3. Changes in RFT slopes:

The authors note that changes in RFT pattern in clinical trials over the duration of intervention studies usually, short term around 3 years of follow-up, may not consistently predict the progression to ESRD; Longer trials 5-10years may be required. Whether these are feasible, fundable or acceptable to Pharmaceutical sponsors in a hurry to market a new drug for CKD is questionable.

4. Patients selection:

RCTs and data analysis as well as showing intervention efficacy may benefit from a careful patients' selection favouring teh inclusion of those with faster rate of GFR decline and overt proteinuria; a faster rate of progression would require a smaller sample size and increased study power.

Also recommended is to have an observational run in phase to determine the nature and rate of the RFT and CKD progression; those with fast (-3-5ml/min/year) and linear negative (RFT) progression rate would also increase the power of the study.

The authors also touch on the most important issue in my mind, namely that fact that eGFR does NOT equate with meassured/true GFR; this was most dramatically shown in the BEAM and BEACON studies, where the impression of an improved eGFR reflected weight loss and anorexia thus changes in creatinine metabolism rather than improving renal function. Ultimately BEACON had to be stopped for toxicity of the compound (Bardoxolone) and excessive morbidity and mortality.

Also the reliability of eGFR/serum creatinine does NOT take into account the impact of renal tubular secretion of creatinine on the changes induced by an intervention on these parameters. Even ACE inhibition may affect tubular secretion of creatinine, a totally neglected variable in RAAS inhibition studies of CKD progression where GFR has seldom been measured????

Finally, when eGFR and mGFR were compared in progressive ADPKD, eGFR based on the MDRD and CKD-EPI equations was found wanting. eGFR changes poorly reflected changes in mGFR. Both formulas underestimated GFR changes by 50%. 

mGFR would be preferable to eGFR, although the authors have argued that variability of a mGFR based on isotopically labelled iothalamate may be high, not withstanding the inconvenience to the patient of measuring GFR and the related cost and time requirements.

One can conclude from this excellent editorial, that to study the impact of interventions on CKD progression the ideal RCT would require:

1. Careful patients selection; preferably with fast progressors who are proteinuric. After all these are the patients who warrant intervention to stop their progression to ESRD.

2. A Run in phase to determine the nature of RFT in patients included in the trial with preference for those with fast and negative but also RFT/slopes.

3. Long follow-up as short studies relying on unpredictable (for long term outcomes/ESRD) endpoints can be misleading.

4. Validating CKD progression parameters by measured GFR as the gold standard. 

Nephrologists need to think carefully and read this editorial before embarking on hastily designed and flawed clinical trials that yield inconclusive or wrongly conclusive results.


[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Meguid El Nahas - Monday, 7 April 2014, 1:29 PM
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A letter to the editor in this month NEJM:

highlights the difference between the outcome of Nephropathic Cystinosis in developed and developing countries.

A survey undertaken by the authors in 17 developing and 13 developed countries showed massive differences in renal survival (ESRD) between the two groups; in fact the outcomes of developing countries nephropathic cystinosis in the 21st century is similar to that observed in developed countries 30 years ago before the advent of cysteamine treatment!

This once more highlights, many issues and problems with healthcare for Orphan and Rare Kidney Diseases (ORKD) in developing countries:

1. Poor awareness

2. Late diagnosis

3. Restricted access to medication 

This in spite of the well known fact and observations that initiation of Cysteamine therapy before the age of 5 years impacts on the progression of cystinosis, renal failure, diabetes, hypothyroidism as well as patients survival.

It is high time the GAP between rich and poor countries is bridged when it comes to healthcare, but for this to be accomplished in ORKD concerted efforts have to be made between Governments, NGO as well as the Pharmaceutical Industry.


[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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There has been much interest in the last couple of years in the potential of renal denervation to manage resistant hypertension particularly after the SYMPLICITY-HTN-2 study was published in the Lancet several years ago.

There have been a number of studies sponsored by medical device companies including SYMPLICITY and EnligHTN that have been active recently. At last we have the data with the publication of SYMPLICITY HTN-3 in the New England Journal of Medicine

In this study patients with severe resistant hypertension (all patients were on the maximum doses of at least 3 drugs including a diuretic) were randomly assigned in a 2:1 ratio to undergo renal denervation or a sham procedure.   The primary end point was change in office blood pressure (probably a poor surrogate for actual blood pressure) and a  secondary endpoint including a safety composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis. A particular strength of the study was that 24 hour ambulatory BP was measured as well as office BP as a secondary endpoint and an impressive 535 patients were included in the study

The bottom line was that there was NO significant difference in the primary endpoint in both groups. Furthermore whilst blood pressure fell significantly in the denervation group it also fell in the sham group ( the mean (±SD) change in systolic blood pressure at 6 months was −14.13±23.93 mm Hg in the denervation group as compared with −11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline) with no significant differences in office BP between the groups.   24 hour ambulatory BP failed to show a positive impact of denervation either: 6.75±15.11 mm Hg fall in BP in the denervation group and −4.79±17.25 mm Hg. Again this difference was not significant.

There were no safety concerns with denervation. Subgroup analysis did not show any positive impact in any subgroup including 10% of patients with 'renal impairment'

The findings are at odds with previous studies such as the unblinded SYMPLICITY HTN-2 trial which showed significant reductions in blood pressure with denervation.

So how come the difference - well what the study highlights is the importance of blinding in a clinical trial. The positive results from earlier trials were from unblinded studies whilst in this study blood pressure fell significantly in the sham-procedure group as well... the reasons of this aren’t clear but we know that there can be a powerful 'placebo' effect in any clinical study. In medical device studies 'sham' interventions are the equivalent of the placebo or control arm - yet such sham interventions are often not performed for 'ethical' reasons of not wanting to subject patients to a sham-intervention that maybe associated with risk to the patient. Yet SYMPLICITY HTN-3 clearly demonstrates the absolute necessity for having such a sham-intervention group when evaluating the impact of medical devices.  The reasons underlying the BP fall in the sham group aren’t clear but we know that being enrolled in any clinical trial often brings improvements even in the control/placebo arm. This may simply be as a result of increased contact with medical professionals resulting in improved patient adherence in medications and general good care.

Enthusiasts for denervation may say that one of the problems is that the radiologist has no 'read out' to tell them whether denervation has been successful and this may account in part for these disappointing results. However ablation catheter used in the SYMPLICITY HTN-3 study was no different from that used in the SYMPLICITY HTN-1 and HTN-2 studies.

My colleague Will McKane who has considerable expertise in denervation tells me that he has anecdotal experience of denervation being a huge success in some patients with resistant hypertension with some patients achieving good control on minimal medication after years of intractable, severe hypertension.  Indeed the standard deviations indicate that there can be a very broad response to denervation and so it is possible that a positive impact of denervation in selected patients was ‘hidden’ in the mass of data from the trial. However we don’t have good evidence to support this nor is there anyway of identifying those who may respond.

As was pointed out in an accompanying editorial in NEJM there has been enormous hype around denervation with many claiming it to be a potential ‘cure’ for hypertension. That bubble has now burst and at the moment its difficult to see any significant future for denervation in the management of resistant hypertension

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

Kidney Int. 2014 Mar 5. doi: 10.1038/ki.2014.48. [Epub ahead of print]
Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing.
Brown EJ1, Pollak MR2, Barua M3.
Author information
The haploid human genome is composed of three billion base pairs, about one percent of which consist of exonic regions, the coding sequence for functional proteins, also now known as the 'exome'. The development of next-generation sequencing makes it possible from a technical and economic standpoint to sequence an individual's exome but at the cost of generating long lists of gene variants that are not straightforward to interpret. Various public consortiums such as the 1000 Genomes Project and the NHLBI Exome Sequencing Project have sequenced the exomes and a subset of entire genomes of over 2500 control individuals with ongoing efforts to further catalog genetic variation in humans.1 The use of these public databases facilitates the interpretation of these variant lists produced by exome sequencing and, as a result, novel genetic variants linked to the disease are being discovered and reported at a record rate. However, the interpretation of these results and their bearing on diagnosis, prognosis, and treatment is becoming even more complicated. Here, we discuss the application of genetic testing to individuals with focal and segmental glomerulosclerosis (FSGS), taking a historical perspective on gene identification and its clinical implications along with the growing potential of next-generation sequencing.Kidney International advance online publication, 5 March 2014; doi:10.1038/ki.2014.48.



This is a recently published, and a must read, review by Martin Pollak and colleagues. It takes the readership smoothly through the “uneasy” world of genetic testing in nephrotic syndrome (NS) and FSGS: why, when, how, who, which?

The authors go through the genetic causes of NS and FSGS including slit diaphragm, actin cytoskeleton, nuclear, glomerular basement membrane, and other genes e.g. APOL1. Nevertheless the authors did not come across the mitochondrial genes, an important entity being potentially treatable, as their main focus was nonsyndromic NS/FSGS.

Not only clinical implications of identifying a disease causing mutation in NS patient as to therapeutic intervention and transplantation strategy is discussed, but also the highly controversial area of testing the clinically unaffected members of a family with hereditary NS and the psychological ramifications that come along!

It all boils down to the wise and thoughtful use of genetic testing with considerations of its risks and benefits, and an understanding of its limitations in general as well as advantages and limitations of different procedures employed: Sanger sequencing, exome or genome sequencing, and the targeted sequencing by using panels of genes which has recently been increasingly implemented. In the latter, sequencing a panel of genes rather than the entire exome or genome allows the clinician/researcher to focus, with less complex, less time consuming and rather cheaper data interpretation.

Gained knowledge from this fascinating area of research in molecular genetics is immensely and rapidly growing, perhaps more than any other field in medicine. DNA sequencing technology is advancing at such a rapid pace, yet the challenge will always be how to translate this knowledge in terms of elucidating the pathogenesis of variable and complex renal diseases, in the best interest of affected patients and their families.


[ Modified: Thursday, 1 January 1970, 1:00 AM ]
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by Meguid El Nahas - Sunday, 16 February 2014, 2:44 PM
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Blog By Dr Sherif AlHammady (Edited by Prof El Nahas)


My advice to you if you are optimistic about the era of guidelines is to read the BMJ article:



The BMJ in a series of article on Guidelines, and their value as well as issues with transparency and conflict of interest, highlights the ways the pharmaceutical industry influence the thrust of many guidelines. It often starts with the selection of panellists on guidelines committees; the overwhelming majority of committee chairs and co-chairs have ties to industry, and selection of panellists with industry-friendly viewpoints can make a desire outcome a foregone conclusion. Committee stacking may be one of the most powerful and important tools to achieve a desired outcome. Although guidelines are usually issued by large panels of key opinion leaders (KOL), the BMJ articles highlight to their careful selection by the industry as well as the choice of single issue fanatics (SIF) who are uncritically wedded to a dogma to which they steer the guidelines panels towards. A recent survey found that 71% of chairs of clinical policy committees and 90.5% of co-chairs had financial conflicts (2).

 Take the LIPIDFS GUIDELINES as an example:

(a)   In 2004, cholesterol guidelines greatly expanded the number of people for whom treatment is recommended. A firestorm broke out when it was learnt that all but one of the guideline authors had ties to the manufacturers of cholesterol lowering drugs (4). 

 (b)   In 2013, the situation doesn't seem much better, as the new lipids guidelines released by the American College of Cardiology–American Heart Association (ACC-AHA) Task Force on Practice Guidelines seem to lower the threshold for prescribing statins based on an unvalidated cardiovascular scoring system.

(c) In 2013, KDIGO also seem equally indiscriminate as to who should receive statins amongst CKD patients…it seems as if statins for all is the flavour of our times…although evidence is seriously lacking…this is often acknowledged by the guidelines themselves awarding 1C or even 2C (NO EVIDENCE) to some of their recommendations; but  all too often unaware physicians take the guidelines at face values and don't seem too concerned about their level of validity or utility…








1-Jeanne Lenzer, medical investigative journalist Why we can’t trust clinical guidelines
BMJ 2013; 346 doi: (Published 14 June 2013) Cite this as: BMJ 2013;346:f3830
2- Kung J. Failure of clinical practice guidelines to meet institute of medicine standards: two more decades of little, if any, progress. Arch Intern Med2012;172:1628-33.
3-Lenzer J, Epstein K. The Yaz men. Washington Monthly2012 Jan 9.
4-Abramson JE, Barnard RJ, Barry HC, Bezruchka S, Brody H, Brown DL, et al. E.petition
to the National Institutes of Health seeking and independent review panel to re-evaluate
the national cholesterol education project guidelines. 2004.
finalnihltr.pdf. Cite this as: BMJ 2013;346:f3830© BMJ Publishing Group Ltd 2013


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