User blog: Meguid El Nahas

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In this month November 2012, AJKD:

Am J Kidney Dis. 2012 Nov;60(5):804-11. doi: 10.1053/j.ajkd.2012.06.017. Epub 2012 Jul 25.

Albuminuria, Estimated GFR, Traditional Risk Factors, and Incident Cardiovascular Disease: The PREVEND (Prevention of Renal and Vascular Endstage Disease) Study.


Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.



Abnormal levels of both albuminuria and estimated glomerular filtration rate (eGFR) have been reported separately to be associated with cardiovascular risk. This study assessed the contribution of each separately in correctly identifying individuals at cardiovascular risk in the general population beyond traditional risk markers.


Prospective community-based cohort study.


8,507 individuals from the city of Groningen in the Netherlands followed up for 10.5 years for cardiovascular morbidity and mortality.


The contribution of albuminuria and eGFR separately on top of the traditional Framingham risk factors was assessed.


The composite of first occurrence of myocardial infarction, stroke, ischemic heart disease, revascularization procedure, and all-cause mortality.


At the baseline visit, albuminuria was measured in 2 consecutive 24-hour urine samples. eGFR was calculated using the serum creatinine-based CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.


In multivariable Cox regression models, albuminuria, but not eGFR, was associated independently with the primary study outcome (HR, 1.08 [95% CI, 1.04-1.12] per doubling of albuminuria). When added to the risk model consisting of Framingham risk factors, albuminuria significantly contributed to better risk stratification, shown by an increase in net reclassification index of 7.2% (95% CI, 3.3%-11.0%; P < 0.001) and increase in relative incremental discrimination improvement of 3.0% (95% CI, 0.9%-5.1%; P = 0.006).


The cohort includes mainly individuals of European ancestry. Therefore, results should not be extrapolated to other ethnicities.


In a general population cohort, albuminuria, but not eGFR, significantly adds to traditional cardiovascular risk factors in identifying individuals at risk of cardiovascular morbidity and all-cause mortality.



This very interesting piece of research from the PREVEND group shows what was suspected and alluded to by others

(Clase et al

and Chang & Kramer, 2010):

that eGFR doesnt improve the predictive value of a Framingham Risk Score (FRS) for CVD and related mortality. This supports what I have argued all along that low eGFR in the community reflects underlying atherosclerosis and ischemic renal damage most often associated with the ageing process.

and therefore it is not surprising that is predicts underlying CVD and their outcomes. CKD is in fact a target organ consequence of CVD. So no surprise that CKD predicts CVD and its outcomes but so does a good history taking, physical examination or a Vascular Risk Score like the FRS.

I argued the same for microalbuminuria; that it is merely a urinary reflection of ill health in the community. The Urine ESR or CRP.... This may also be attributable to age related atherosclerosis and vascular dysfunction. So it would not be suprising that a marker of CVD predicts overt CVD and its complications in the community!!!!

However, the study of Smink and Colleagues from Groningen seem ti imply that albuminuria adds to the predicitve value of the FRS. It improves the Net Reclassification Index (NRI) by 7.2%. Interestingly, it doesnt seem to improve the prediction of those who go on to experience an fact it worsens the FRS predictive value by -2.8% in those.....but it improves the predictive value of those who do NOT experience an event....So my reading would be FRS in the absence of albuminuria is good news!!!!! But adding albuminuria to FRS worsens rather than improve the FRS prediction model?????

So for people in the community at risk of CVD, the FRS is most accurate in predicting major CV events and associated mortality.

Neither eGFR nor Albuminuria improve its positive predictive value.

Take a good history and Examine your patients do derive a good prediction model of CVD and outcomes.

Neither eGFR or microalbuminuria add much to good clinical prediction models. On their own they are predicitive of CVD and related mortality as they reflect underlying CVD in communities, but when compared or added to strong and established CVD prediction models they add nothing or little....!!!!






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by Meguid El Nahas - Wednesday, 21 November 2012, 9:33 AM
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The UK ADDITION study of value of screening for DM has reported its findings in the Lancet.

This was a clinic level cluster randomised trial.

>16,000 high risk individuals were screened in general practice in the UK between ages of 40-69 for type2 diabetes mellitus.

3% were found to have DM upon screening.

Follow-up of 10 years of these cohorts showed no difference in mortality between screening and control group. 

Moratlity hazard ratios for death from CVD, cancer and diabetes did not differ either.

The study has not reproted on microvascular complications and their incidence.


The low prevalence of 3% of T2DM in this high risk population may be a reason why the overall impact of screening on mortality has been limited. In populations with higher prevalence of obesity and T2DM, screening of those at risk may prove cost-effective.

Also, screening may allow to detect early complications of T2DM such as renal, cardiovascular, neuropathic and ocular involvements. These may take more than 10 years to fully express their morbidity and the associated mortality. Early detection may impact on progression of microvascular complications and overall outcomes in the longer term. Such secondary prevention of complications have not been reported by the ADDITION study yet.

Ultimately, the issue of obesity and T2DM is a societal one and one that involves primary prevention. Here lifestyle changes are key to outcomes but implementation of societal lifestyle changes take much more that mere encouragement to eat well and excercise....!!! Also barriers for implementation of lifestyle and metformin treatment for prevention of T2DM has previously been discussed on OLA.

Finally, lifestyle changes require huge economical commitments from governments with changes in internal migration, westernisation as well as urbanisation. It also requires urban planning with changes in the configuration of our communities and cities...In the current financial climate of recession and austerity, governments have other priorities on their minds....

Interesting to read in the Lancet this week about New York city efforts to reduce NCDs:

As New York City Mayor Michael Bloomberg has noted, “while government action is not sufficient alone, it is nevertheless absolutely essential. There are powers only governments can exercise, policies only governments can mandate and enforce, and results only governments can achieve. To halt the worldwide epidemic of non-communicable diseases, governments at all levels must make healthy solutions the default social option. That is, ultimately, government’s highest duty.








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by Meguid El Nahas - Friday, 16 November 2012, 6:57 AM
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This is a post by Dr Pierre Delanaye posted on OLA French that I translated and share in view of its importance:

Biological variability and critical difference are concepts of clinical biology nephrologists often poorly familair with, but are essential for clinicians and clinical decision making.


Variability of a biomarker (eg serum Creatinine, or PTH) is the intra-individual coefficient of variation (CVi) without taking into account the analytical variability (due to imprécisison of the measurement = CVa). One could say that the CVi is the variability of a marker or a biological that is "normal" or physiological. It is determined by measuring from the same patients, for example, the marker at 1-week intervals for 6 weeks. The subject is compared each time itself.
The critical difference integrates the CVi and CVa and represents the change needed to be reached for the change in value in the same patient longitudinal monitoring to be considered significant. For example, with serum creatinine, it is around 10-15% (depending on the method used and its CVa). This means that for a given patient, if two successive values ​​of creatinine did not reach 15%, these results are in fact superimposable and "not different".
The critical difference for serum PTH as we have determined (publication pending) is 40-50%! which is huge. This means a difference of more than 50% between PTH values ​​for a patient to say that it has truly changed...!!!!
These concepts are important to grasp to assist with decision making when changes in a biomarker can trigger a clinical management decision.
+ See also the very interesting work of our English colleague EJ LAMB
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by Meguid El Nahas - Monday, 5 November 2012, 3:53 PM
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Tolvaptan in Patients with Autosomal

Dominant Polycystic Kidney Disease

Vicente E. Torres, M.D., Ph.D., Arlene B. Chapman, M.D.,
Olivier Devuyst, M.D., Ph.D., Ron T. Gansevoort, M.D., Ph.D.,
Jared J. Grantham, M.D., Eiji Higashihara, M.D., Ph.D., Ronald D. Perrone, M.D., Holly B. Krasa, M.S., John Ouyang, Ph.D., and Frank S. Czerwiec, M.D., Ph.D., for the TEMPO 3:4 Trial Investigators*



The course of autosomal dominant polycystic kidney disease (ADPKD) is often associ-

ated with pain, hypertension, and kidney failure. Preclinical studies indicated that

vasopressin V -receptor antagonists inhibit cyst growth and slow the decline of kidney



In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we ran- domly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V2-receptor antagonist, at the high- est of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.


Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow- up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (recip- rocal of the serum creatinine level, −2.61 [mg per milliliter]−1 per year vs. −3.81 [mg per milliliter]−1 per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher dis- continuation rate (23%, vs. 14% in the placebo group).


Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercial- ization; TEMPO 3:4 number, NCT00428948.)

n engl j med

The New England Journal of Medicine November 2012.


Very exciting and promising results on the slowing of the progression of ADPKD with preserved kidney function by a ADH V2 receptor antagonist; Tolavptan.

Previous interventions with mTOR antagonists (Sirolimus and Everolimus) have shown that kidney size increase can be pharmacologically manipulated, improved, in ADPKD. Tolvaptan is also effective in that respect.

However, the TEMPO study shows, that unlike mTOR antagonists, V2 blockage by Tolavptan can slow the progression of CKD in ADPKD.

Some reservations regarding the latter point:

1. The impact on kidney function was not a primary endpoint, so the study may not be fully powered to look at that variable?!

2. Glomerular filtration rate was NOT measured but instead calculated (eGFR). It was shown by Remuzzi and his colleagues that such analysis can be misleading in ADPKD :

3. The study was also conducted on ADPKD patients with normal kidney function where the estimated GFR tend to be at best inaccurate.

4. The effect of ADH antagonisms on tubular secretion of creatinine is unknown? Could the observed effect related to changes in tubular handling of creatinine rather than GFR. After all ADH impacts on tubular secretion of uric acid another OCT mediated tubular handled substance.

It is high time nephrologists and their sponsor who undertake multimillion pounds/dollars RCTs on CKD progression MEASURE CKD progression.....not serum creatinine!





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by Meguid El Nahas - Thursday, 1 November 2012, 5:04 PM
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Chronic Kidney Disease—A Challenge for All Ages .

Ian H. de Boer, MD, MS. JAMA. Published online October 30, 2012. doi:10.1001/jama.2012.30761

Context:  Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial.

Objective:  To evaluate possible effect modification (interaction) by age of the association of eGFR and albuminuria with clinical risk, examining both relative and absolute risks.

Design, Setting, and Participants:  Individual-level meta-analysis including 2 051 244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australasia, Europe, and North/South America, conducted in 1972-2011 with a mean follow-up time of 5.8 years (range, 0-31 years).

Main Outcome Measures:  Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholesterol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates.

Results:  Mortality (112 325 deaths) and ESRD (8411 events) risks were higher at lower eGFR and higher albuminuria in every age category. In general and high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age; eg, adjusted HRs at an eGFR of 45 mL/min/1.73 m2 vs 80 mL/min/1.73 m2were 3.50 (95% CI, 2.55-4.81), 2.21 (95% CI, 2.02-2.41), 1.59 (95% CI, 1.42-1.77), and 1.35 (95% CI, 1.23-1.48) in age categories 18-54, 55-64, 65-74, and ≥75 years, respectively (P <.05 for age interaction). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0-12.8], 12.2 [95% CI, 10.3-14.3], 13.3 [95% CI, 9.0-18.6], and 27.2 [95% CI, 13.5-45.5] excess deaths per 1000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age was less evident, while differences in absolute risk were higher in older age categories (7.5 [95% CI, 4.3-11.9], 12.2 [95% CI, 7.9-17.6], 22.7 [95% CI, 15.3-31.6], and 34.3 [95% CI, 19.5-52.4] excess deaths per 1000 person-years, respectively by age category, at an albumin-creatinine ratio of 300 mg/g vs 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories.

Conclusions:  Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risk differences at older age.


The reported increased risk of mortality associated with low eGFR (<60ml/min) and albuminuria in all age group including the elderly is not surprising.

This is because older patients with low eGFR (<60ml/min) also have underlying CVD, clinically detectable or subclinically, as shown by Park and colleagues recently:

Otherwise, why on earth would an older patient have declining GFR without proteinuria?! The Baltimore Aging Longitudinal Study (BALS) study implied that those whose kidney function decline with age have co-morbidities most often hypertension. Lindeman et al.

The problem with the above study is that underlying CVD, and in particular hypertension, are not factored in these analyses of hazard risk in relation to low eGFR and mortality. Hypertension, for example, is neither adequately diagnosed, treated or controlled worldwide; to take the US example, only around 60% of hypertensive individuals are treated....and 35% are shown by Chobanian:

Furthermore, in most of the studies quoted in the above analysis, BP is seldom measured and when it is, it is not measured adequately. It is measured at the office and casually, measurements known to be of little correlation with CV outcomes and mortality. Night time, home and 24h ambulatory BP measurements are nowadays thought to be more predictive of CVD outcomes when compared to office BP monitoring. 

So it is not surprising that older individuals with poorly treated and uncontrolled hypertension have a higher prevalence of target organ damage including CKD. It is also not surprising that they have a higher risk of CVD and related death.

So my take on this paper is that those older people who are at higher risk of death because of low eGFR, are at higher risk because low GFR is a MARKER of underlying CVD NOT a maker of risk....I would also argue that underlying CVD is not properly, if at all, assessed in these individuals.

When CVD risk is properly assessed the NIR (added predictive risk) of renal markers (eGFR and albuminuria) to the standard CVD risk markers is NIL...

As to low level albuminuria, it is probably a reflection of underlying hypertension or diffuse vascular damage!

So once more, the authors do not seem to discern the fact that CKD most likely reflects underlying age-related atherosclerosis/CVD and hypertension (clinical or subclinical-diagnosed or undiagnosed) and therefore it is not surprising that older people with these abnormal markers have a higher mortality....!!!!! 


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by Meguid El Nahas - Friday, 19 October 2012, 11:40 AM
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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!



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.


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by Meguid El Nahas - Wednesday, 17 October 2012, 10:13 AM
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Read this weeks Lancet 13th of October 2012:
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. 
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 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!
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by Meguid El Nahas - Thursday, 6 September 2012, 2:16 PM
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An interesting article in the BMJ by Prof Yudkin and colleagues in London is entitled:

"The Idolatry of Surroagtes"

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!

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.


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by Meguid El Nahas - Tuesday, 4 September 2012, 7:58 AM
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In this week (September 1-7, 2012: 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....).


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:

Also, as previously shown in a number of studies reviewed by Chang and Kramer in 2011 (, 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) (

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...!!!



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by Meguid El Nahas - Friday, 31 August 2012, 7:08 AM
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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.



Asymptomatic adults without diagnosed chronic kidney disease (CKD)


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

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

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


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