## User blog: Meguid El Nahas

Anyone in the world

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

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

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

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

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

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

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

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

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

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

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

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

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

Anyone in the world

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

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

Pharma also brings planeloads of delegates to attend these meetings.

Pharma organises symposia and workshops.

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

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

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

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

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

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

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

Perhaps, Nephrologists dont know better...

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

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

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

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

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

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

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

Anyone in the world

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

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

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

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

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

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

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

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

Data Summary

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

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

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

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

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

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

Comment:

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

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

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

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

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

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

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

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

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

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

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

So far the lessons of clinical translation in ADPKD:

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

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

Anyone in the world

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

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

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

OLA BLOG COMMENT:

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

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

Instead, they equate to changes in serum creratinine levels.

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

Dietary intake

Muscle mass and Creatinine metabolism

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

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

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

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

Similar misrepresentations of eGFR are contaminating our literature.

One such example:

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

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

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

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

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

and

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

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

Anyone in the world

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

A number of reminders have recently highlighted such dilemmas.

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

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

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

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

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

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

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

The questions I really ponder are:

1. Is science directly translatable to public health policies?

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

3. Are public health policies effective?

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

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

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

Anyone in the world

Intensive glucose control improves kidney outcomes in patients with type 2 diabetes.

### Source

The George Institute for Global Health, University of Sydney, Sydney, New South Wales, Australia.

### Abstract

The effect of intensive glucose control on major kidney outcomes in type 2 diabetes remains unclear. To study this, the ADVANCE trial randomly assigned 11,140 participants to an intensive glucose-lowering strategy (hemoglobin A1c target 6.5% or less) or standard glucose control. Treatment effects on end-stage renal disease ((ESRD), requirement for dialysis or renal transplantation), total kidney events, renal death, doubling of creatinine to above 200 μmol/l, new-onset macroalbuminuria or microalbuminuria, and progression or regression of albuminuria, were then assessed. After a median of 5 years, the mean hemoglobin A1c level was 6.5% in the intensive group, and 7.3% in the standard group. Intensive glucose control significantly reduced the risk of ESRD by 65% (20 compared to 7 events), microalbuminuria by 9% (1298 compared to 1410 patients), and macroalbuminuria by 30% (162 compared to 231 patients). The progression of albuminuria was significantly reduced by 10% and its regression significantly increased by 15%. The results were almost identical in analyses taking account of potential competing risks. The number of participants needed to treat over 5 years to prevent one ESRD event ranged from 410 in the overall study to 41 participants with macroalbuminuria at baseline. Thus, improved glucose control will improve major kidney outcomes in patients with type 2 diabetes.

# Commentary

Kidney International (2013) 83, 346–348; doi:10.1038/ki.2012.431

## Intensive glycemic control in type 2 diabetics at high cardiovascular risk: do the benefits justify the risks?

Sabin Shurraw1,2 and Marcello Tonelli1,2

1. 1Department of Medicine, University of Alberta, Edmonton, Canada
2. 2Alberta Kidney Disease Network, Canada

Correspondence: Marcello Tonelli, Department of Medicine, University of Alberta, Alberta Kidney Disease Network, 7-129 Clinical Science Building, Edmonton, Alberta T6B 2G3, Canada. E-mail: mtonelli-admin@med.ualberta.ca

Top

### ABSTRACT

Perkovic et al. use novel data from the ADVANCE study to report on the potential renal benefits of standard glycemic control, compared with intensive glycemic control (mean hemoglobin A1c 7.3 and 6.5%, respectively). Intensive glycemic control reduced the risk of new-onset microalbuminuria, new-onset macroalbuminuria, and progression of albuminuria. The risk of end-stage renal disease was also reduced in patients treated with intensive glycemic control, although the number of events was small.

Most guidelines, including those from the Kidney Disease Outcomes Quality Initiative (K/DOQI) (National Kidney Foundation), suggest that glycemic control is an important clinical objective for all diabetic patients with and without chronic kidney disease (CKD). These guidelines recommend a target hemoglobin A1c of approximately 7.0% ‘to prevent or delay complications of diabetes, including diabetic kidney disease,’ noting that more intensive treatment improves albuminuria, but evidence for any effect on loss of glomerular filtration rate (GFR) is sparse.1

Perkovic et al.2 (this issue) explore the potential benefits of intensive glycemic control for renal outcomes, using a post hoc analysis of the ADVANCE trial. ADVANCE3 randomly assigned 11,140 patients to standard glycemic control following local guidelines versus intensive glycemic control (target A1c6.5%). Included patients had type 2 diabetes (average duration 8 years) and were more than 55 years old (average age 66 years). Only patients at high risk were included, based on a history of major macrovascular disease, microvascular disease (overt nephropathy or retinopathy), or one major cardiovascular risk factor. After a median duration of 5 years, mean A1c was 7.3 vs. 6.5%, respectively, in the two groups. There was no difference in the risk of macrovascular events between groups (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.84–1.06, P=0.32). However, patients who were in the intensive glycemic control group had fewer microvascular events (HR 0.86, 95% CI 0.77–0.97, P=0.01), primarily due to a 21% reduction in ‘new or worsening nephropathy’ (HR 0.79, 95% CI 0.66–0.93, P=0.006); there was no effect on retinopathy.

The new analysis by Perkovic et al.2 begins by providing us with more insight into the prevalence of preexisting renal disease in the 11,140 ADVANCE participants. At baseline, approximately 27% of patients had microalbuminuria (an inclusion criterion) but only 3.6% had macroalbuminuria. Most patients had no CKD (55%), while CKD stages 2 and 3 was present in 15% and 19% of patients, respectively. Advanced CKD (stages 4 and 5) was present in 0.5% of all patients. As expected based on the main finding of ADVANCE, outcomes related to proteinuria appeared more favorable with intensive glycemic control: new-onset microalbuminuria (33.5 vs. 36.3%), new-onset macroalbuminuria (3.0 vs. 4.3%), and progression of albuminuria by 1 stage (23.3 vs. 25.3%) (allP<0.012). Patients treated with intensive glycemic control had more regression of albuminuria by 1 stage (61.2 vs. 56.3%) and more regression to normoalbuminuria (56.3 vs. 50.2%) (all P0.002).

The authors acknowledge that albuminuria is of questionable reliability as a surrogate marker for renal outcomes and appropriately focus on the risk of end-stage renal disease (ESRD). In these new analyses, the risk of ESRD was significantly reduced in patients treated with intensive glycemic control (vs. standard treatment) (HR 0.35, 95% CI 0.15–0.83, P=0.017). Furthermore, patients with preexisting renal disease seemed to derive more benefit from intensive glycemic control as reflected by a lower number needed to treat (NNT): the NNT was 152 for any albuminuria, 147 for estimated GFR <60ml/min, 85 for estimated GFR <60ml/min per1.73m2 with any albuminuria, and 41 for macroalbuminuria (irrespective of GFR). These findings were consistent in various subgroups, including participants with baseline A1c above or below median (7.2%), with or without retinopathy, in both assigned blood pressure treatment groups (ADVANCE was a two-by-two factorial trial of glycemic and blood pressure control), both men and women, and with age above or below median. On the basis of these data, the authors suggest that intensive glycemic control (presumably A1c <6.5% as targeted in ADVANCE) may be a useful strategy to prevent the development of ESRD in patients with type 2 diabetes.

Before widespread adoption of such a strategy, the reader should consider some important aspects of this post hoc analysis. First, despite an apparent reduction in the risk of ESRD with intensive glycemic control, there was no significant effect on serum creatinine over time—only a non-significant trend toward more frequent doubling of serum creatinine (to >200μmol/l) in intensively treated patients (HR 1.15, P=0.42). The authors propose that doubling of serum creatinine may be an imprecise ‘surrogate’ for progression of diabetic nephropathy to ESRD, as it may capture patients suffering acute kidney injury due to sepsis, shock, and so on. In support of this hypothesis, there was a non-significant trend toward lower risk of sustained doubling of serum creatinine with intensive glycemic control (HR 0.83,P=0.38). Nonetheless, the possibility remains that other factors besides intensive glycemic control per se contributed to the apparent reduction of the risk of ESRD in the treatment group. For example, patients in the (unblinded) intensive treatment arm might have been observed more closely by their treating physician—which in turn could have reduced the risk of acute kidney injury or its consequences.

Second, the number of patients who developed ESRD during ADVANCE was exceedingly low (27 events in 11,140 patients=0.24%). This contributed to the high NNT (445 patients to prevent one case of ESRD over 5 years)—although the NNT was lower in patients with more advanced CKD at baseline, likely because of the higher absolute risk in this group. Despite the high quality of the analyses, the small number of events may reduce confidence in the findings.

The results of ADVANCE and the current analysis by Perkovic et al.2 must be interpreted in the context of other randomized controlled trials that have assessed the impact of intensive glycemic control on clinically relevant kidney outcomes. ACCORD was similar to ADVANCE and enrolled 10,251 patients with type 2 diabetes and high cardiovascular risk (>40 years old with known cardiovascular disease, or >55 years old with anatomical evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two cardiovascular risk factors), with randomization to conventional glycemic control (A1c 7.0–7.9%) versus an even more intensive regimen targeting A1c <6%.4 This trial was terminated early (after 3.5 years) because of increased mortality in intensively treated patients. However, a subsequent analysis reported on renal end points at trial’s end.5 Intensive glycemic control resulted in lower A1c at one year (median 6.4 vs. 7.5%) and, similarly to ADVANCE, resulted in a 20–30% reduction in the risk of new-onset micro- and macroalbuminuria, but no reduction in the risk of doublings in serum creatinine (in fact, a significant increase: HR 1.07, P=0.016)—and, in contrast to the results reported by Perkovic et al.,2 no decrease in ESRD (HR 0.95, 95% CI 0.73–1.24, P=0.71). The most recent randomized trial of intensified glycemic control, VADT, was published in 2009 and enrolled 1791 military veterans with long-standing type 2 diabetes (mean duration 11.5 years), 40% of whom had known cardiovascular disease.6 Patients were randomized to standard therapy versus intensified glycemic control to decrease A1c by 1.5%; A1c between groups was 8.4 vs. 6.9%. After a median of 5.6 years, there was no difference in the risk of mortality or microvascular end points, other than a reduced risk of progression of albuminuria; the risks of doubling of serum creatinine and stage 5 CKD were similar between groups (P=0.99 and P=0.35, respectively).

What can we conclude about the effect of glycemic control on diabetic nephropathy in type 2 diabetes, and, more broadly, on patient survival and cardiovascular events? We believe that it is reasonable and generally safe to target an A1c of 7%. The UK Prospective Diabetes Study (UKPDS) showed that early, more intensive glycemic control (A1c of 7.0 vs. 7.9%) in patients with newly diagnosed type 2 diabetes safely reduced microalbuminuria and doubling of serum creatinine (as well as retinopathy).7

So, should clinicians routinely target an A1c of 6–7% or lower? As discussed, high-quality data from ACCORD, VADT, and ADVANCE all demonstrate that this strategy will improve proteinuria-based surrogate outcomes, but only the post hoc analysis of ADVANCE by Perkovic et al.2 suggests that such an intensive strategy may reduce the clinically relevant outcome of ESRD. However, adopting an intensive glycemic control strategy may also pose risks to patients. A1ctargets below 6.5% led to increased mortality (largely due to myocardial infarction) in ACCORD and had no significant effect on cardiovascular events or mortality in ADVANCE.

One may speculate that patients enrolled in the latter two trials, most of whom had established type 2 diabetes and major cardiovascular risk factors, were more susceptible to the adverse consequences of hypoglycemia, as opposed to the younger, healthier UKPDS participants. Similarly, observational data suggest that achieved A1c<6.5% is associated with excess mortality in patients with diabetes and established CKD.8

Thus, intensive glycemic control appears to have both risks and benefits—and despite the important findings of Perkovic et al.,2 this strategy cannot be broadly recommended at present. Current data do not allow clinicians to confidently identify patients in whom the risk-to-benefit ratio of tighter glycemic control is especially favorable. Until such data are available, we suggest that an A1c target <6.5% for type 2 diabetes should be used cautiously, if at all—perhaps only in well-informed patients who are younger, at lower risk for hypoglycemia, and free of symptomatic cardiovascular disease.

OLA COMMENTARY:

This is an excellent and balanced review of the recent publication on a posthoc analysis of ADVANCE putting in the context of other intensive v conventional glycemia control stuides in T2DM.

It highlights the facts that in high risk T2DM patients:

1. Intensive glycemia control with HbA1c <7% is either associated with no CVD benefit or increase mortality (ACCORD)

2. Intensive glycemia control has NO effect on renal HARD ENDPOINTS such as decline of GFR or incidence of ESRD

3. Observational studeis also suggest increased mortality with HbA1c<6.5%

The study commenetd upon by Perkovic et al also highlights a number of issues:

1. The concern about endless mining of data to find positive results in posthoc analyses. These are at best hypothesis generating (difficult when considerable data suggest the opposite...) or at worst futile and misleading excercises.

2. The distinction between statistical analysis and the true clinical value of such observations; p vale <0.05 but number needed to treat to prevent 1 ESRD 445 patients over 5 years!!!!!

3. The use of serum creatinine as a marker of progressive CKD/DN, in elderly patients with CVD and a tendency to sarcopenia; thus dissociating further changes in sCr = eGFR and true measured GFR and true progression of Diabetic nephropathy. Intensive glycemia control with its induced side effecst and increased morbidity may be associated with a fall in sCr hence the apparently stable sCR in the Perkovic study in spite of possible worsening of true GFR/kidney function....?!

4. The use of ESRD in the absence of measured GFR as a hard endpoint; this can be misleading and observer baised as the decision to start RRT often has subjective elements to it; a good example of such dissociation was seen in REIN studies where in patients with reduced GFR<45; Ramipril had NO effect on measured GFR decline but decreased the number of those reaching ESRD....!!

http://www.ncbi.nlm.nih.gov/pubmed/10437863

5. Glycemia control may improve/lower sCr through improved on the impaired tubular secretion of Cr observed and associated with DM. http://www.ncbi.nlm.nih.gov/pubmed/15882297

http://www.ncbi.nlm.nih.gov/pubmed/12753302

6. The disconnect between reduction of albuminuria and progression of diabetic nephropathy/CKD; most of the studies showing that intensive glycemia control benefit albuminuria but NOT progression of kidney function decline. This may reflect that glycemia control can affect albuminuria in many ways unconnected to slowing the decline in GFR.

7. Lowering glycemia can improve urianry albumin excretion in the following way:

a. Increasing CVD morbidity and decreasing protein intake due to poor health; this would in turn reduce albuminuria that is often proportional to the protein intake.

b. Affecting glycation and charge of albumin which in turn decrease its filtration and reabsortion rates. http://www.ncbi.nlm.nih.gov/pubmed/9187409

http://www.ncbi.nlm.nih.gov/pubmed/8477883

c. Improving peritubular circulation an dimproving proximal tubular reabsorption of albumin; many beleive that microalbuminuria in DM is a reflection of vascular and fall in peritubular capillary perfusion impacting/decreasing proximal tubular reabsorption of albumin.

http://www.ncbi.nlm.nih.gov/pubmed/22734110

http://www.ncbi.nlm.nih.gov/pubmed/21401356

ALTOGETHER,

IT IS MISLEADING TO CLAIM PROTECTION FROM PROGRESSIVE DIABETIC NEPHROPATHY THROUGH THE REDUCTION IN ALBUMINURIA AND UNRELATED BIOMARKER.

IT IS MISLEADING TO EQUATE CHANGES IN SCR INDEPENDENTLY OF THE HARD ENDPOINT OF MEASURING GFR.

START OF RRT/ESRD IS DIFFICULT TO INTERPRET IN THE ABSENCE OF HARD DATA RELATING TO TEH RATE OF DECLINE OF KIDNEY FUNCTION.

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

Anyone in the world

Prevalence of Diagnosed Cancer According to Duration of Diagnosed Diabetes and Current Insulin Use Among U.S. Adults With Diagnosed Diabetes Findings from the 2009 Behavioral Risk Factor Surveillance System

Authors :CHAOYANG LI,GUIXIANG ZHAO,XIAO-JUN WEN,EARL S. FORD, LINA S. BALLUZ,
org DIABETES CARE
Diabetes Care Publish Ahead of Print, published online January 8, 2013

this article recently published in diabetes care raises suspicious about long term insulin use in T2DM and cancer .
The aim of the study was to To determine whether longer duration of diagnosed diabetes and current insulin use are associated with increased prevalence of cancer among adults with diagnosed diabetes,
Authors analyzed a large population-based sample from the 2009 Behavioral Risk Factor Surveillance
System (BRFSS) in the U.S. The BRFSS is a standardized telephone survey that assesses key
behavioral risk factors, lifestyle habits,and chronic illnesses and conditions among adults aged $18 years in all U.S. RESULT :There were a total of 34,424 adults with diagnosed diabetes participating in the survey with the diabetes module. Of them, 8,460 had missing data on diabetes age, insulin use, and selected covariates. Among adults with diagnosed diabetes and with complete data on cancer and diabetes-related covariates (n = 25,964), there were 11,165 men (weighted percentage, 52.8%), 18,673 NH whites (65.3%), 3,575 NH blacks (16.0%), 2,348 Hispanics (13.1%), and 1,368 participants with NH other race/ ethnicity (5.6%). Approximately 4.7% of adults with diagnosed diabetes were estimated to have type 1 diabetes (n = 491 men and 721 women), 70.5% were type 2 diabeticwithout current insulin use (n = 7,820 men and 10,475 women), and 24.8% were type 2 diabetic with current insulin use (n = 2,854 men and 3,603 women). The mean age was 58.6 years (median 59.0 years). The mean age at diabetes diagnosis was 47.6 years (49.0 years). The unadjusted prevalence for cancers of all sites among men with type 2 diabetes and current insulin use was higher than those with either type 1 diabetes (P , 0.001) or those with type 2 diabetes and no current insulin use (P , 0.001) among both men and women. After adjustment for age, the difference in the prevalence estimates for cancers of all sites remained between adults with type 2 diabetes with current insulin use and those with type 2 diabetes with no current insulin use among men (P , 0.001) and women (P , 0.001). Among both men and women with type 2 diabetes, the prevalence estimates for cancers of all sites were significantly higher among those who had diabetes >15 years than among those who had diabetes ,15 years after adjustment for all selected covariates . Specifically,the prevalence was estimated to be significantly higher among adults who had diabetes$15 years for colon cancer, melanoma, nonmelanoma skin cancer, and cancer of urinary tract among men and the cancers of the breast, female reproductive tract, and skin among women than those who had diabetes ,15 years. Among both men and women with type 2 diabetes, the prevalence estimate for cancers of all sites was ~1.5 times higher among those who used insulin than those who did not use insulin after adjustment for demographic characteristics and selected health risk factors.
current insulin
use remained significantly associated with increased prevalence of cancers of all sites among both men and women and increased prevalence of skin cancer (both melanoma and nonmelanoma) among men and cancer of the reproductive tract .

1-The relation between Insulin use and cancer needs more attention and further .Further research may be warranted.
2-The major strength this study was the use of a large population-based sample,
which enabled investigators to provide stable estimates of cancer prevalence among adults with diabetes in the general population.
3- There were also several limitations , the study is a cross-sectional study in which persons who self-reported diagnosed cancer were cancer survivors and included those who were newly diagnosed and those who had a preexisting condition. Persons who died of cancer were excluded in this self-reported cross-sectional survey. Therefore, these results based on the prevalence of diagnosed cancer suggest crosss ectional associations and preclude causal associations between duration of diagnosed
diabetes or current insulin use and cancer.
4-Age at diagnosis of diabetes or cancer, current insulin use, and cancer types were self-reported by survey participants; thus, recall bias may be possible.
5-duration of diagnosed diabetes may not represent actual duration of exposure to diabetes because people may be asymptomatic for many years before medical diagnosis.

However and again this study raised the red flag between possible association between insulin and cancer that was raised before for Lantus.

Professor Alaa Sabry
[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Anyone in the world

American Society for Critical Care Medicine (Puerto Rico): January 22, 2013

GFRs Overestimated in ICU Patients with AKI

Glomerular filtration rates (GFRs) of critically ill patients with acute kidney injury (AKI) are routinely overestimated, data presented at the Society for Critical Care Medicine's 2013 annual meeting suggest. Investigators believe urine output should be used instead of creatinine-based equations to assess kidney function in oligoanuric ICU patients.

The average baseline serum creatinine level was 0.9 mg/dL, and 10% of subjects had a documented history of chronic kidney disease. On each of the first four days of AKI, patients were between 1.8 and 3.7 liters fluid positive. Ten percent of the patients were prescribed trimethoprim.

The researchers assumed that the patients had a true GFR of less than 15 mL/min/1.73 m2. They compared this to the patients' estimated GFRs (eGFRs) calculated from six existing equations. The equations were the Cockcroft-Gault using actual body weight (CG-ABW), Cockcroft-Gault using ideal body weight (CG-IBW), Jeliffe, Modified Jeliffe, the four-variable Modification of Diet in Renal Disease (MDRD-4) study formula, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations.

Results of all six equations significantly overestimated GFR, even after the researchers adjusted for patients' daily variation in creatinine clearance. The closest approximation of the true GFR was given by the CG-IBW, which yielded a day-adjusted eGFR of 32 ml/min/1.73m2. The next-most accurate was the CG-ABW, with a day-adjusted eGFR of 51 ml/min/1.73m2. The least accurate was the Jeliffe equation, with a day-adjusted eGFR or 65 ml/min/1.73m2. Statistically and clinically significant overestimation of true GFR persisted out to the fourth day of AKI.

The findings echo those of previous studies. For example, a multicenter observational study published in 2010 showed the CG-ABW, MDRD and Jeliffe equations overestimated urinary creatinine clearance by 80%, 33% and 10%, respectively (Nephrol Dial Transplant 2010;25:102-107).

Clearly, this doesnt fully appreciate that:

1. eGFR (Regardless of the CR based Formula used) is NOT applicable to AKI!

2. eGFR is NOT applicable to non-steady state situations!

3. eGFR is NOT applicable to sick patients with malnutrition and sarcopenia!

4. Serum Creatinine is an UNRELIABLE marker of true GFR/Kidney Function in AKI!

Other Biomarkers are not much better and a circular argument goes that they rise before serum Cr goes up....but serum creatinine is an unreliable marker of AKI...so in the absence of Gold Biomarker for AKI, clinical judgement is key to the Diagnosis and Management of AKI!

http://ndt.oxfordjournals.org/content/early/2012/10/31/ndt.gfs380.full.pdf+html

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

Anyone in the world

Mohan and colleagues in the December issue of JASN report on the prognostic value of pre-transplant DSA (Donor Specific Antibodies) measured by solid phase assays (SPA) in relation to renal allografts outcomes. Mohan et al. JASN 2012;23:2061-2071.

They undertook a systematic review of cohort studies comprising a total of 1119 patients inclduing 145 with isolated DSA-SPA.

They noted that in the presence of negative Complemenet dependent cytotoxicity (CDC) crossmatch, a positive DSA-SPA (such a Luminex) doubles the risk of antibody-mediated rejection (AMR) and increases the risk of long term graft failure. This suggests that recipients should be checked for DSA regardless of a negative cross match. Of interest, the negative impact of a positive DSA-SPA test at transplantation on outcomes was noted regardless of the SPA titre (mean fluorescence index: MFI, low 1000).

This observation is in agreement with previous publications:

For instance, Lefaucheur and colleagues in 2010 showed that patients with MFI >6000 had >100-fold higher risk for AMR compared to those with MFI <465. The presence of HLA-DSA did not affect patients survival. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938596/

Gary Hill and colleagues in Paris showed that DSA+ recipients have a three fold increase incidence of renal arteriosclerosis. Such accelerated arteriosclerosis was noted early within teh course of the allograft (3-12 months after transplantation). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083319/

1. Interesting observation consistent with the literature on the topic.

2. How would routine DSA-SPA screening affect outcomes?

This may stratify patients into higher risk warranting stronger initial/induction immunosuppression with ATG/Alemtuzumab.

It may also trigger closer monitoring of DSAs after transplantation and lead to related maintenance immunosuppression related strategies.

Alternatively, DSA screening would be undertaken if and when AMR is suspected; onset of albuminuria for instance!

3. Is routine DSA-SPA of all transplant recipients cost effective?

4. Are all DSAs harmful?

5. Is detection of DSA-SPA antibodies of unknown significance create unecessary investigations, excessive testing and unecessary patients' anxiety?

Is this a luxury few renal transplantation centres can afford or is it a game changer in renal transplantation?

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

Anyone in the world

Professor Richard Glassock wrote:

Thank Dr Khwaja your for your passionate plea for declaring that access to high-quality healthcare (including life-extending procedures such as dialysis and transplantation for those who suffer from ESRD) is a human right not a privilege.  Such a position was codified 65 years ago in the Universal Declaration of Human Rights adopted by the UN General Assembly (Article 27)—mentioning adequate but not high-quality health care and avoiding the issue of cost.

In the face of limited resources, difficult choices must be made on how to extend this right of access toadequate health care to the maximum extent possible across the broad spectrum of health problems in a given society (the burden of disease).

Surely the socio-economic status of individuals suffering from the consequences of ill-health should never be a criterion for making such difficult choices in a civilized society. Nevertheless, the winners in the lottery of life (the affluent) will always have a privileged status in regards to their access to the health care game.  What you have written about is the dilemma of what to do for those who did not win the lottery of life, by virtue of birth or circumstances.

Societies and the governments they form must make these difficult choices for the populations they are entrusted to serve (or oppress as the case may be).  We all recognize that chronic kidney disease (CKD) and its end-stages can be a debilitating and devastating development for individuals, but on a population basis it ranks rather low compared to other common non-communicable health issues, and it tends to disproportionately affect the elderly.  According to the Global Burden of Diseases (2010) study recently reported in Lancet (volume 380, December 15, 22, 29, 2012) in a landmark series of papers, CKD ranked 39th for years lived with disability among 289 diseases and injuries (average of 58 years lived in disability per 100,000 population--low back pain and major depression ranked 1st and 2nd).  In 2010 CKD ranked  24th in a list of 235 causes of death (up from 32nd in 1990) in terms of global years of life lost, but 7th among non-communicable disease (up from 10th in 1990). Not surprisingly, ischemic heart disease ranked  1st in this category.  Among the top 10 ranked disorders in terms of global years of life lost, 6 were communicable, 3 were non-communicable and 1 was related to injury.  The global ranking of CKD (including ESRD), in terms of years of life lost, ranged from 6th (in Central Latin America) 36th (in Central sub-Saharan Africa.

While these details do not truly reflect the degree of human suffering brought about by CKD or any other disease, they do provide a useful perspective in the challenging arena of choice-making from the societal perspective. Resource-rich countries such as North America and Western Europe have adopted a variety of strategies to deal with the burden of disease in their unique regions.  The United Kingdom adopted a strategy of universal access and “free” at the point-of- car for all of its citizens after WW II (The National Health Service; NHS); whereas the United States more recently adopted a  non-universal, capitalistic (free-market) framework, focusing on the elderly, the disabled and the poor.  The Affordable Care Act (“Obamacare”) is extending this reach into a broader range of its citizens, but it still does not approach the NHS in terms of universality of access, except in the arena of ESRD care. Many resource-poor countries have naturally focused on common health issues arising from communicable diseases, such as water potability, vaccination, and endemic infectious diseases (e.g. HIV and Malaria).  The ever-present threats or realities of war have also had a bearing on allocation of scarce resources for health. Many countries are now in transition from a pre-occupation with communicable diseases to the non-communicable ones, especially as their populations age, consequent to lower birth rates and better control of  life-threatening infectious disease.

Yes, the percentage of gross domestic product allocated to diagnosis and treatment of disease varies widely among the countries of the world.   The large amounts of money spent in resource-rich countries does not always result in a uniformly high quality of life and excellent outcomes of care.  Also, in a capitalistic society there is always the opportunity for fraud and abuse and in socialist schemes the implicit risk of rationing by the queue. Universal care cannot be equated with “free” care- it is merely a formalized way of redistributing capital in the form of taxation policies.  As we are learning in the USA, if we are to guarantee access of high-quality health care to everybody, either our taxes must increase or the cost of the care-provided, in aggregate, must come down. The latter means fewer units of care and /or a lower cost per unit.  Where does care for CKD or ESRD fit in this new equation, and how will other less affluent populations grapple with the disconnect between the burden of care, in its varied forms, and the ability of governments (or individuals) to sustain the funding of care, without the prospect of insolvency?  A middle ground must be sought, but some form of rationing, implicit or explicit, seems inevitable.

In the case of CKD and ESRD, like ischemic heart disease, stroke and COPD, an effort to prevent disease or slow its progression is certainly a wise choice, considering the alternatives.  Improvements in the care of patients with ESRD already under treatment with dialysis or transplantation, will improve the quality of life, but will also steadily increase the number of patients treated (like better survivorship with cancer chemotherapy), at least until some new balance is achieved between incidence rate and death rates among the treated population.  Global screening of asymptomatic persons for the presence of CKD in the population as a whole does not seem to be a viable option at the present, but efforts to detect and control Obesity, Diabetes and Hypertension may be a cost-effective way of lowering the burden of CKD in vulnerable populations, and would have the added benefits of addressing issues in ischemic heart disease, stroke, blindness, amputations and congestive heart failure that contribute so much to the global burden of disease.  Such an approach need not have CKD as it central theme.

An organized, coherent, simple and universally-agreed upon system of classification, nosology and staging of CKD is a highly desirable goal- and much progress has been made by KDOQI in 2002 and KDIGO in 2012.  However, this system must in the final analysis, in the perspective of optimal allocation of resources in rich and poor countries alike, accurately identify those individuals most likely to benefit from interventions and at the lowest achievable cost.   There should be a low tolerance for both “false positives” and “false negatives”, especially when disease labeling can have untoward consequences and when erroneous reassurance leads to damaging delays in appropriate treatment.

You make a plea that organized Nephrology couple their advocacy for logical classification of CKD (largely based on prognosis) and clinical guidelines with a strong message that care for patients with kidney disease be universally available, publically supported (“free” at the point-of –care) and of the highest-quality.

Assuredly, you must recognize that such advocacy, on a global stage, creates the necessity for agonizingly difficult decisions involving prioritization among a list of equally or more pressing problems of health in an environment of limited or soon-to-be limited resources. In addition, other social issues such as education, poverty, war and its prevention are competitive to health issues.  Surely access to adequate health care is a right, and not a privilege for the fortunate few, but the expression of this right by populations, through their governments should be leavened by reason and by the ethical principle of the providing the greatest good for the largest number, without consideration of the social worth of the individual.  Physicians adhere to the traditional medical ethic of “rendering to each patient a full measure of service and devotion” Foregoing such a “full measure” can be easily justified when the treatment is useless or unnecessary.  Similar decisions can be fraught with much difficulty (and risk) when such “full measure” competes with broader social issues.  It is the tension in this complex arena that you address in your poignant and passionate essay.

Richard J. Glassock, MD, MACP

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