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There is an interesting publication in JASN online by Remuzzi’s group looking at the effect of angiotensin II inhibition on glomerular vasculature. They use micro-CT and scanning EM to study the effect of RAS inhibition in Munich Wistar Fromter (MWF) rats that spontaneously develop kidney disease with age. Untreated MWF rats develop glomerusclerosis and interstitial fibrosis and micro-CT data showed a reduction of spatial density in arteries and veins in the kidney - in essence a reduction in vascular volume relative to total kidney volume. This effect was reversed by treatment with losaratan and lisinopril which the authors describe as regeneration of the vasculature on the basis that vascular volume increased once treatment started. Scanning electron microscopy data appeared to show that RAS blocked increased glomerular capillary (GC) volume and length. The authors state that this results in increased functional GC and thereby increasing filtering surface area. Losartan and Lisinopril both appeared to reduce mRNA expression of profibrotic mediators such as TGFbeta and endothelin as well as reducing the expression of alpha-smooth muscle actin in both glomerular and interstitial capillaries - which the authors take as a sign of inhibition of endo-mesenchymal transition.

RAS blockade also inhibited endothelial cell apoptosis and increased Nrf2 expression -Nrf2 is thought to be a mediator of endothelial cell dynamics and angiogenesis. In summary the authors conclude that RAS blockade has anti-fibrotic effects via TGFbeta and endothelin (these have been well described in the literature in in vivo and in vitro models) coupled with the angiogenic effects of RAS blockade seen in this model highlights the ‘regenerative’ ability of anti-RAS agents.
My brief thoughts:
i) striking that there was no control group treated with an other anti-hypertensive - therefore impossible to know whether the histological and vascular changes were a RAS blockade-specific effect or a generic effect of lowering blood pressure - I’m very surprised that the reviewers in such a high impact journal didn’t insist that the authors at least acknowledge this point.
ii) this lack of blood pressure control is even more worrying when making claims that RAS blockers can promote regression of glomerusclerosis - we all know that in patients with accelerated hypertension there is regression of glomerular changes with improved blood pressure control.
iii) the EM data is very difficult to interpret and the conclusions made by inferring changes in physiology on the basis of morphological changes seem too simplistic to me .
iv) the whole story is just all too ‘neat’ - RAS blockers inhibit fibrosis via TGFbeta and promote vascular ‘regeneration’ by effects on endothelial cell apoptosis and endothelial-mesenchymal transition and… bingo you have a regenerating kidney. Yet the reality is that these models of kidney disease (e.g. MWF) don’t replicate the complexity of kidney disease in humans where multiple insults (ischaemia, diabetes, hypertension, smoking and ageing) all combine to produce CKD which is usually non-progressive and doesn’t, as the authors suggest, lead ‘invariably to ESRD’. If the story was so simple then the widespread use of RAS blockers would have ‘solved’ the problem of ESRD - yet it clearly hasn’t. Indeed the real world data suggest that these agents maybe positively harmful in certain settings or have absolutely no impact on progression particularly in the elderly population. Furthermore data from the NEPHRON D study (as well as in ONTARGET)  showed that the increased risk of AKI/dialysis with aggressive RAS blockade far outweighed any hypothetical benefits on organ fibrosis - and this is a phenomena not just seen in clinical trials but also in the real world as highlighted by this analysis of primary care admissions.
 
In summary RAS blockers are excellent anti-hypertensive agents. They have risks in certain patient groups (e.g. elderly arteriopaths with ischaemic nephropathy) and whilst they maybe be able to slow down progression of certain kidney diseases as a result of tight BP control, the idea they they can lead to clinically meaningful ‘regeneration’ of fibrosed kidneys seems, to me, fanciful.
 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Tuesday, 30 June 2015, 8:31 AM
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Lancet. 2015 Apr 25;385(9978):1634-41. doi: 10.1016/S0140-6736(14)62053-5. Epub 2015 Jan 23.

Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial.

Abstract

BACKGROUND:

Hypertension contributes to cardiovascular morbidity and mortality. We assessed the safety and efficacy of a central iliac arteriovenous anastomosis to alter the mechanical arterial properties and reduce blood pressure in patients with uncontrolled hypertension.

METHODS:

We enrolled patients in this open-label, multicentre, prospective, randomised, controlled trial between October, 2012, and April, 2014. Eligible patients had baseline office systolic blood pressure of 140 mm Hg or higher and average daytime ambulatory blood pressure of 135 mm Hg or higher systolic and 85 mm Hg or higher diastolic despite antihypertensive treatment. Patients were randomly allocated in a 1:1 ratio to undergo implantation of an arteriovenous coupler device plus current pharmaceutical treatment or to maintain current treatment alone (control). The primary endpoint was mean change from baseline in office and 24 h ambulatory systolic blood pressure at 6 months. Analysis was by modified intention to treat (all patients remaining in follow-up at 6 months). This trial is registered with ClinicalTrials.gov, number NCT01642498.

FINDINGS:

83 (43%) of 195 patients screened were assigned arteriovenous coupler therapy (n=44) or normal care (n=39). Mean office systolic blood pressure reduced by 26·9 (SD 23·9) mm Hg in the arteriovenous coupler group (p<0·0001) and by 3·7 (21·2) mm Hg in the control group (p=0·31). Mean systolic 24 h ambulatory blood pressure reduced by 13·5 (18·8) mm Hg (p<0·0001) in arteriovenous coupler recipients and by 0·5 (15·8) mm Hg (p=0·86) in controls. Implantation of the arteriovenous coupler was associated with late ipsilateral venous stenosis in 12 (29%) of 42 patients and was treatable with venoplasty or stenting.

INTERPRETATION:

Arteriovenous anastomosis was associated with significantly reduced blood pressure and hypertensive complications. This approach might be a useful adjunctive therapy for patients with uncontrolled hypertension.

FUNDING:

ROX Medical.

COMMENTS:

This pilot study pertains to treat resistant hypertension by the creation of an iliac AV shunt...

Whilst seemingly promising, it is another example of the BIG INDUSTRIAL MEDICAL COMPLEX intrusion into clinical practice; the use of a potentially harmful, not to say dangerous, interventions to treat patients who may not need it (those whose SBP is above 140mmHg, whilst their age if over 70....) or who may be controlled otherwise...by a 4th antihypertensive agent...or better compliance...25-30% of so called resistant hypertensives are non compliant:

http://www.ncbi.nlm.nih.gov/pubmed/24694797

The AV shunt intervention exposes patients to a number of serious complications such as DVT as well as potential ischemic lower limb changes...

It is also an example of the BIG INDUSTRIAL MEDICAL COMPLEX influence on publishers...the publication in the Lancet, a seemingly serious journal, of a pilot study with short and inadequate follow-up as well as devoid of control/sham intervention group not to mention compliance to medical checks... In other words, a pilot, proof of concept, study with a number of serious limitations...published in a top medical journal...?!

This intrusion of the INDUSTRIAL MEDICAL COMPLEX was already demonstrated in patients with "resistant" hypertension by the Renal Sympathetic Denervation (RDN) clinical trials, SIMPLICITY...mostly badly designed an uncontrolled until SIMPLICITY HTN 3 showed no benefit...

BUT...the MEDICAL INDUSTRIAL COMPLEX...doesnt rest its case but pursue and encourage the greed of interventionists amongst private physicians...who saw in such method a major source of unethical income...by all sorts of subgroup analyses and posthoc analyses claiming benefits...:

in Japan: http://www.ncbi.nlm.nih.gov/pubmed/26102846

In subgroups: http://www.ncbi.nlm.nih.gov/pubmed/24914028

Younger patients: http://www.ncbi.nlm.nih.gov/pubmed/25565369

Non-African Americans...

Number of bursts...

https://www.gkaonlineacademy.com/blog/item/simplicity3-not-so-simple

etc...

In other words, the MEDICAL INDUSTRIAL COMPLEX feeds on:

1. Pseudo clinical indications

2. Poorly managed patients, by conventional means

3. Credulous physicians who think any new technology is an advance...

4. Greedy physicians who make money out of new interventions at the expense of their patients' safety or benefit...in countries where private medicine thrives...

5. Medical Journals attracted by medical technical innovations...even when poorly designed, or pilot, studies underpin the findings...

IT IS HIGH TIME WE, AS A PROFESSION, PUT PATIENTS BENEFIT AND SAFETY BEFORE GADGETRY AND PROFIT...

 

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

Is There a Real Global Epidemic of Chronic Kidney Disease?

Numerous publications have asserted that the global prevalence of chronic kidney disease (CKD) in adults is generally between 10-13% (as determined from the KDOQI or KDIGO Classification schema, but using one-off, non-age calibrated determinations for identification of CKD ) and that the burden of this disease has reached “epidemic” proportions.  In some developed countries (e.g. USA) the population-based prevalence rate of CKD has levelled off, at least in most adult age groups, and some countries have a much lower prevalence of CKD (e.g. Italy) than the global averages.  A new and monumental study has put a fresh perspective to the issue of the global burden of CKD (Global Burden of Disease Study 2013 Collaborators, The Lancet, June 8, 2015 – on-line).  This seminal study of the incidence, prevalence and years lived with disability (YLD) for 301 acute and chronic diseases (including CKD) and injuries in 188 countries during 1990 and 2013 sheds new light on the purported “epidemic” CKD.  The data (35,620 distinct sources) were derived and analyzed in a fashion different from those publications using KDOQI or KDIGO criteria so they may not be strictly comparable.  The inclusion of both adults and children may have also altered the prevalence data compared to KDOQI and KDIGO, which are confined to adults only.

Nevertheless the observations are quite informative.   There were 324,666,000 cases of CKD in 1990 and 471,916,000 cases of CKD in 2013; after adjusted for aging and population growth the prevalence rate of CKD (per 100,000 population) actually declined overall by about  5% between 1990 and 2013.  But the change in adjusted global prevalence rate between 1990- and 2013 was not uniform among the causes of CKD; to wit, the adjusted global prevalence rates of CKD due to glomerulonephritis and hypertension declined by 13.54% and 10.74% respectively whilst the adjusted global prevalence rates of CKD due to diabetes or other causes increased by 11.85% and 3.12% respectively.  If the global population was 7.1 Billion in 2013 about 6.7% had some form of CKD; about 20% of which could be attributed to diabetes.  The inclusion of children in both the denominator and numerator in this analysis may have diluted the overall prevalence rates of CKD, to some degee. But taken at face value, these figures indicate that generic CKD as a whole is not occurring in “epidemic” proportions globally, but that there are very worrisome trends over the last 2 decades in that CKD due to diabetes is a major and growing global problem.     Correspondingly, the  reported age and population standardized YLD rose by 10.6% and 6.9% for CKD due to Diabetes and other causes respectively between 1990 and 2013 whilst the  age and population YLD fell 22.4% and 6.9% for CKD due to hypertension and glomerulonephritis respectively for a net decline in the YLD burden of CKD on a global basis.

Translating these intriguing findings into an action plan for control of the global disease burden linked to CKD is a difficult task and undoubtedly the answers will be different for developing compared to developed nations and depend greatly on the importance of CKD relative to other public health priorities (e.g. electrification, potable water, infectious disease, etc).  What does seem abundantly clear, at least to me, is that the focus should not be on generic CKD, but rather on the problem of diabetes and its parent obesity.  In my opinion, what the globe urgently needs is a coherent, culture-adapted approach to detection, prevention and management of obesity and diabetes (“diabesity”)—and not a population- based early detection program for generic CKD.  Furthermore, more research leading to better understanding and treatments for the complex triad of obesity, diabetes and CKD are greatly needed. We should recognize that a global epidemic of generic CKD simply does not exist and relentlessly devote our energy to mitigating the world-wide problem of too many calories of the wrong kind and lack of energy consuming activities so as to avoid the CKD complications of “diabesity”.  

Richard J. Glassock, MD

Geffen School of Medicine at UCLA

 June 8, 2015

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

Prof Richard Glassock wrote in reference to the latest publication in the Lancet on the Global Burden of Disease Study 2013: (The Lancet On line 8th of June 2015)

It represents massive data collection and a complicated analysis but the main message is that except for diabetes related  CKD, most forms of CKD are decreasing (since 1990) in total prevalence and years lost to disability. 

The only "epidemic" of CKD is that related to diabetes, and indirectly to obesity. 

The public health authorities around the world should not be focusing on detection of CKD, per se, as a problem, but instead should be energetically trying to curtail diabetes, by focusing on its origins; diet (composition and energy content) and activity level. 

Claims that the world is trapped in an out-of-control epidemic of CKD represent mis-information at its worst, as these claims obfuscate the real issue; diabetes and its micro- and macro-vascular complications. 

Screening programs for CKD are socially irresponsible, if they detract from addressing the real problem- diabesity (diabetes due to obesity), a potentially preventable disorder-- easily detected but difficult to treat.

Food for thought!!!

My Comments:

The global "epidemic" of CKD has been an ill founded concept based on very poor epidemiology and/or rather poor biostatistics.

http://www.ncbi.nlm.nih.gov/pubmed/23497858

This had a number of consequences, that I condemn:

1. Raised awareness of CKD, but overinflated its scale...claiming to affect 1 in 2 individual over a lifetime…

2. Medicalised the ageing process, by falsely claiming that CKD affected millions over the age of 65...thus confusing true CKD with age-related decline in kidney function…

3. Generated an industry of lightweight biostatistical analyses based on poorly collected and seldom validated data…published as irrefutable facts…

http://www.ncbi.nlm.nih.gov/pubmed/23588748

http://www.ncbi.nlm.nih.gov/pubmed/23497858

4. Raised the profile of Nephrology as a subspeciality, but at the price of misinformation...or to be kind, an unfounded truth...

http://www.ncbi.nlm.nih.gov/pubmed/23727165

5. Increased “Nephrologists” income in countries where their income stems from recognising, diagnosing, and cashing on, false diseases in an alarmed and misinformed population…

6. Failed to distinguish true CKD from community based older individuals with reduced kidney function…

7. Overburdened Nephrologists worldwide by unnecessary referrals of older patients with mild to moderate, but stable, age-related impaired kidney function; thus distracting them from their true task of dealing with primary and progressive nephropathies!

8.  Increased prescription of potentially nephrotoxic agents such as ACE inhibitors in the elderly without a shred of evidence that it protected from early CKD progression or delayed ESRD, and in spite of evidence to the contrary:

http://www.ncbi.nlm.nih.gov/pubmed/24424348

9. Generated more diseases, namely AKI, in elderly individuals prescribed ACE inhibitors for dubious and ill founded indications…:

http://www.ncbi.nlm.nih.gov/pubmed/?term=tomson+C%2C+AKI%2C+ACE+inhibitors

10. Overlooked the true burden of disease; namely Hypertension and Diabetes, thus leaving them significantly under-diagnosed and under-treated!

Shame on us as a professional body to have jumped uncritically on this bandwagon…

”Castles built on sand, soon collapse…”

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Sunday, 7 June 2015, 2:23 PM
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Blog based on a lecture by Professor Samir Mallat at the Global Kidney Academy Master Class held in Prague on 7 June 2015.

SIMPLICITY HTN3 showed no effect of renal sympathetic denervation (RSD) on the control of hypertension.

Subgroup analyses of SIMPLICITY3 suggest that the effect may not be as negative as initially thought:

1. Those <65y may respond to RSD

2. Non African Americans may respond to RSD

3. Those NOT on alpha blockers may respond to RSD

4. The number of ablation bursts >10 may be beneficial

5. The circumferential denervation may be most effective

http://www.ncbi.nlm.nih.gov/pubmed/25744017

Consequently, more studies are planned.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Simplicity+3+study%2C+resistant+hypertension

Is that good clinical research, following leads from posthoc and subgroup analyses, to establish new evidence?

or

is it the perseverance of the medical industrial complex that has invested heavily in that technology and doesnt want to ditch it...?

along with

medical practitioners who saw a potential source of income and private practice and dont want to give it up...?

The verdict is out...

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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JAMA. 2015 May 29. doi: 10.1001/jama.2015.6731. [Epub ahead of print]

An Age-Calibrated Classification of Chronic Kidney Disease.

 
COMMENTS:

 The most practical way to separate age-related decline in eGFR from that associated with bona-fide kidney disease might be a persistent dipstick proteinuria of > 1+. While somewhat lacking in sensitivity it has reasonable specificity.  One needs to be careful about use of urine albumin to creatinine ratios (UACR) in the elderly as the expected decline in creatinine excretion with age (and frailty) leads to overestimation of albumin excretion, and thereby mis classification when one uses a KDIGO advocated schema.

 
The effect of ancestry and ethnicity on the age related changes in measured GFR or eGFR are not well studied.  Fitness and frailty, independent of ancestry or ethnicity, probably have a greater effect on eGFR (based on serum creatinine values). To my knowledge, the age-related decline in eGFR is seen in all ancestries, ethnicities but the rate of decline may vary, perhaps a consequence of the baseline nephron endowment at birth. The frequently cited Baltimore Longitudinal Study of Aging (BLSOG) was not a study of GFR per se, it was a study of true creatinine clearance and an unstated # of Type 2 diabetics were included-- it is not a useful study to examine the decline in eGFR in "healthy aging".  The findings of the BLSOG are frequently misquoted.  The cross-sectional data in very healthy subjects (living donors) strongly suggests that a decline in the functioning nephron population and whole kidney GFR is a fundamental biological phenomenon intimately entangled with organismal aging (organ senescence).  To designate an isolated decline in eGFR (using any equation you choose) to values less than 50% of that present in a healthy 20 year old without any other features of kidney damage as a disease per se is a mistake, in my judgement.
 
Richard Glassock
 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Arif Khwaja - Friday, 29 May 2015, 7:02 PM
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A quick update from the late clinical trials session from the ERA-EDTA which was a high quality session

Jurgen Flöege presented data from the german STOP-IgA Nephropathy trial. Full details of the protocol can be found here but in essence patience patients with proteinuric IgA nephropathy were enrolled into 6 months of best medical care - ACEi,ARBs (aiming for a BP target of 125/75mmHg), statins and low salt+protein diet. After 6 months those with greater than 0.75g/24 hours of proteinuria were randomised to continuing supportive care or immunosuppressive therapy-this consisted of  steroids ( 6 months therapy for those with a GFR>60)  or cyclophosphamide an steroids with a switch to azathioprine after 3 months (for those with a GFR<60 with prednisolone and azathioprine continued for 3 years).
309 patients were recruited to the run in phase of the study but perhaps the most important result of the study was the finding that 34% of patients in the run-in phase weren’t eligible for the active part of the study - i.e. tight BP control alone reduced proteinuria significantly and therefore they did not meet the criteria for immunosuppression.
The 2 key primary endpoints were:
i) full remission defined as <0.2g/24hours of proteinuria and stable renal function (eGFR loss less than 5 mL/min at the end of 3 years compared to baseline
ii) GFR loss>15mls/min from baseline at the end of the 3 years.
Those who were immunosuppressed were 5 times as likely to go into remission ( as defined by criteria above) as those on supportive care but there was NO difference in those with greater than 15mls/min/1.73m2 loss of eGFR between the two groups. Furthermore there were 50% more infections in the immunosuppression and significantly worse glycemic control and new onset diabetes. Immunosuppression appeared to achieve clinical remission predominantly in those with lower proteinuria.
In summary we clearly need to wait for the full paper to look at the data more closely but this study highlights i) the paramount importance of really tight BP control in IgA nephropathy ii) suggests that immunosuppressive therapy has little effect on eGFR progression/deterioration and iii) immunosuppression has a significant cost in terms of morbidity without any clear positive impact on progression.
The second study was a fascinating and really well conducted RCT from Zarbock and colleagues in Germany which looked at the effect of remote ischaemic preconditioning (RIPC) in patients at high risk of AKI (based on Cleveland Clinic Scoring system) after cardiac surgery. Patients with a renal transplant or those with CKD4/5 were excluded. RIPC consisted of inflating BP cuff on the arm 3 times prior to surgery for 5 minutes each time. Anaesthetic protocols were standardised
The primary endpoint was AKI within the first 72 hours (defined using the AKI staging system based on creatinine) - AKI rates were 37% in the RIPC group vs 52.5% in the control group (p<0.002). This was associated with a significant reduction in those requiring RRT though it wasn’t clear if the criteria for RRT was standardised. Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor–binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery. The authors speculate that the release of  damage associated molecular patterns (DAMPS) from ischaemic tissue may induce cell-cycle arrest in the tubulo-epithelial cells in the kidney an thereby protect against subsequent ischameic injury. 
Whilst relying on creatinine in AKI is distinctly problematic at the moment there is is no realistic way to measure GFR in the context of a real world study into AKI. RIPC is a cheap and safe intervention… this study suggests its close to being ready to move into the clinical arena as well as evaluating its role in other areas such as perhaps delayed graft function after transplantation.
The third study presented was the VITA-D study from Vienna, which was another excellent, placebo controlled RCT looking at the impact of native vitamin D3 supplementation in new renal transplant recipients with vitamin D deficiency ( vit D levels<20 ng/mL (50 nmol/L)). The primary endpoints were infection and rejection rates and allograft function at 12 months. Secondary endpoints included change in bone density as measured by DXA from baseline and 12 months.  203 patients were enrolled into the study. There was no impact  of vitamin D supplementation on any of the primary or secondary endpoints. Furthermore in the per protocol analysis kidney function ( as measured by serum creatinine) had a tendency to be worse in the vitamin D arm and this effect was independent of any hypercalcaemia. Again GFR was not measured so difficult to know what to make of this. The authors sensibly concluded that their study showed that there was no evidence of any benefit of D3 supplementation and possible evidence of harm in transplant patients.
The 4th study was a phase 2 study presented by Professor de Zeuuw looking at the effect of CCX140 ( a CCR2 inhibitor - CCR2 being the receptor for monocyte chemotactic protein 1, MCP1) in patients with albuminuria and CKD (eGFR>25mls/min) and type 2 diabetes. There appeared to be a very early effect on albuminuria ( as measured by ACR) of nearly 25% by 12 weeks. The effect appeared to be less with the 10mg dose compared to the 5mg dose which is hard to explain. Furthermore the speed of the effect on proteinuria makes one wonder what the actual mechanism of proteinuria reduction is and whether there is a hamody namic element. Interestingly in the control arm albuminuria did not change through the course of the study. Furthermore there was no difference in eGFR (GFR wasn’t measured) at the end of the study between the two groups - which again makes me think that albuminuria is a nothing more than a surrogate marker in studies of progression. I am not sure the positive spin of this study by some on the stock market is actually justified.
 
Finally John Cunningham  presented data from 2 phase 2 RCTs looking at the administration of AMG416 for secondary hyperparathyroidism. This is a synthetic peptide, has calcimimetic actions and a half life of 3-5 days in ESRD patients. Hence a dosing schedule of IV administration after each dialysis session was utilised in the study. The bottom line was that the drug worked significantly reduced PTH and FGF23 levels. Whether this translates into patient-centred improvements in outcomes is unknown. Although there were some GI side effects with the drug this seemed less than with cinacalcet. Clearly the danger with using a drug with such a long half life is inducing dynamic bone disease.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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J Am Heart Assoc. 2015 Apr 20;4(4). pii: e001599. doi: 10.1161/JAHA.114.001599.

Persistent High Serum Bicarbonate and the Risk of Heart Failure in Patients With Chronic Kidney Disease (CKD): A Report From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Abstract

BACKGROUND:

Serum bicarbonate varies over time in chronic kidney disease (CKD) patients, and this variability may portend poor cardiovascular outcomes. The aim of this study was to conduct a time-updated longitudinal analysis to evaluate the association of serum bicarbonate with long-term clinical outcomes: heart failure, atherosclerotic events, renal events (halving of estimated glomerular filtration rate [eGFR] or end-stage renal disease), and mortality.

METHODS AND RESULTS:

Serum bicarbonate was measured annually, in 3586 participants with CKD, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. Marginal structural models were created to allow for integration of all available bicarbonate measurements and proper adjustment for time-dependent confounding. During the 6 years follow-up, 512 participants developed congestive heart failure (26/1000 person-years) and 749 developed renal events (37/1000 person-years). The risk of heart failure and death was significantly higher for participants who maintained serum bicarbonate >26 mmol/L for the entire duration of follow-up (hazard ratio [HR] 1.66; 95% confidence interval [CI], 1.23 to 2.23, and HR 1.36, 95% CI 1.02 to 1.82, respectively) compared with participants who kept their bicarbonate 22 to 26 mmol/L, after adjusting for demographics, co-morbidities, medications including diuretics, eGFR, and proteinuria. Participants who maintained serum bicarbonate <22 mmol/L had almost a 2-fold increased risk of renal disease progression (HR 1.97; 95% CI, 1.50 to 2.57) compared with participants with bicarbonate 22 to 26 mmol/L.

CONCLUSION:

In this large CKD cohort, persistent serum bicarbonate >26 mmol/L was associated with increased risk of heart failure events and mortality. Further studies are needed to determine the optimal range of serum bicarbonate in CKD to prevent adverse clinical outcomes.

COMMENTS:

The Nephrology community has been led to beleive with weak evidence that increased serum bicarbonate levels slows CKD progression (1-3). Whilst little doubt exists in Nephrologists' mind that metabolic acidosis in CKD is harmful, increased emphasis has been over the last 5 years on aiming for higher than normal serum bicarbonate levels to slow CKD progression and delay ESRD (1-3).

Now data published this month from a CRIC cohort seems to confirm that impression with patients with CKD and serum bicarbonate levels >26mmol/l have a significant decrease incidence of adverse renal events including ESRD compared to those with sBic <22mmol/l. However, the same cohort study shows an alarming increase in congestive heart failure and death rate in those whose serum bicarbonate levels exceeds 26mmol/l...!!!!

Previous NHANES III observations suggested that low serum Bicarbonate levels <22mmol/l are associated with increased mortality in CKD patients (3).

So it seems to me that optimal serum bicarbonate levels in patients with CKD may be between 24-26mmol/l, thus aiming at minimising CKD progression whilst avoiding metabolic alkalosis and its negative effects on the myocardium resulting in congestive heart failure and death. In other words, keeping serum bicarbonate levels within the middle of the normal range (24-26mmol/l) may prove that moderation is the best option for CKD patients!

References:

1. de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate
supplementation slows progression of CKD and improves nutritional status. J
Am Soc Nephrol. 2009;20:2075–2084.
2. Raphael KL, Wei G, Baird BC, Greene T, Beddhu S. Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans. Kidney Int. 2011;79:356–362.

3. Raphael KL, Zhang Y, Wei G, Greene T, Cheung AK, Beddhu S. Serum bicarbonate and mortality in adults in NHANES III. Nephrol Dial Transplant. 2013;28:1207–1213.

 

 

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

The Gap between Theoretical and Practical/Clinically relevant Nephrology Knowledge grows with the type of teaching and conferences given in emerging countries and elsewhere...

Endless lectures...when the speaker shows off his/her knowledge and doesnt care about how much is useful or retainable by the audience...IT IS HIGH TIME THESE USELESS CONFERENCES STOP AND/OR CHANGE....

It is high time that lectures and conferences are audience centered rather than speakers centered...

Does anybody ask the DELEGATES what they would like to listen to...what their educational needs are...??? NO, instead they are given a form of education that is not targeted to their needs...but instead to the needs...promotion...recognition...of the SPEAKERS...!!!!!

I remember at a meeting, convdentional lecture loaded meeting, asking the delegates on Day 2 questions relating to ALL the lectures they listened to on Day 1...hardly one remembered anything meaningful...????

PASSIVE and UNTARGETED teaching is a waste of time for the delegates...and more so to the patients they meant to treat and translate their knowledge to benefit from...

So WHY is it going on...because of the CHRONIC AND HABITUAL SPEAKERS MAFIA... because of ACADEMIC EGOS...because of the HIDDEN AGENDAS OF NATIONAL AND INTERNATIONAL LEARNED SOCIETIES...because of the NOT SO HIDDEN AGENDA OF BIG PHARMA...

Therefore, this may not change but what can change is the way we perceive and receive these teachings....WITH A CRITICAL MIND...WITH A REFLECTIVE MIND...that allows us to filter the MEANINGFUL from the MEANINGLESS...

And always ask the speaker the 5 WHATS:

1. What is the clinical NEED and need for your lecture?

2. What is the EVIDENCE upon which you base your statements?

3. What is the RELEVANCE of what you teach to MY PATIENTS?

Then..

4. What is the risk versus benefit of what you are teaching us?

5. What is the cost versus benefit of the approach you are recommending?

LETS START THIS PROCESS AND CHALLENGE THE SPEAKER!

(give her examples that you have come across of bad teachers!)

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Saturday, 18 April 2015, 11:48 AM
Anyone in the world

Growing evidence is implicating a genetic absis for CKD in African-Americans linked to mutations in the APOL1 gene. A genetic mutation that served sub-saharan Africans well some 10,000 years ago as it confered trypanolytic activity against trypanosoma brucei...but now comes to cost them a susceptibility to non diabetic CKD including primary and secondary FSGS (1).

More recently, it has also become apparent that such mutations in the APOL1 gene may confer increased susceptibility to renal allograft failure; not as much in black recipients but in relation to balck donors. Renal allografts with APOL1 G1 and G2 mutations variants have considerably shorter allograft survival (2).

Consequently, the question is now raised as to whether Blacks with such AOPL1 mutations should donate their kidneys or not? In two respects, first whether such allograft will have a poorer outcome, second, whether the donor, if young, would be susceptible later in life to a nephropathy on his/her remaining kidney. Those may develop the unfavorable CKD/FSGS phenotype later in life.

This concern applies to both living as well as deceased donors. Two (G1 and G2) APLO1 risk variant kidneys may be avoided or used where expanded criteria donor kidneys are considered, as they have a greater probability of early allograft failure.

In the era of rapid sequencing and PCR based genotyping, time may have come for a better genetic evaluation of kidney donors (3).

However, such  approach whilst affordable and applicable in high economies is unlikely to be either practical or affordable in low and middle economy countries where most black individuals and those of African ancestry live...all too often medical guidelines and recommendations made in Western countries and Western publications overlook the fact that the world is not confined to the West, but also East and South...in those, genotyping of any kind is not an option, whilst renal transplantation may be a survival option in the absence of other forms of renal replacement therapies such as dialysis. Instead, a more careful clinical and laboratory evaluation of black donors is warranted, with careful family history (of CKD) souhgt, a careful evaluation of their kidney function and microalbuminuria, as well as more cautious, or agressive, management of these potentially higher risk of failure kidneys. 

References:

1. Genovese et al. Science 2010;329:841-45.

2. Reeves-Daniel et al. Am J Transpl 2011;11:1025-30.

3. Freedman and Julian. Kidney Int 2015; 87:671-73.

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