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by Arif Khwaja - Friday, 8 April 2016, 9:30 AM
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Whilst the benefits of transplantation are well established, finding suitable donors for ‘sensitised’ patients with anti-HLA antibodies remains a significant barrier to transplantation. The options for such patients are to stay on the deceased donor waiting list, participate in the paired+pooled donation scheme (and hope they get a donor) or undergo densistisation and transplant from a live HLA incompatible (HLAi) donor. However the outcomes HLAi live donor transplantation are significantly worse than those receiving compatible kidneys. In reality given the chances of receiving an HLA compatible transplant are so slim, the choice these patients face is to either be desensitised and receive an HLAi live kidney or remain on dialysis.

In a recent publication in NEJM Orandi and colleagues from John Hopkins look at the real world outcomes for such patients in elegant observational analysis. They looked at the outcomes of 1025 kidney transplant recipients (from 22 centres) who received a kidney from an HLAi live donor. As there are significant differences in  the techniques used to measure HLA antibodies they looked ONLY at patients who underwent perioperative densistisation for donor-specific antibodies ( the treatment protocols were not analysed as there was centre to centre variation).
They then compared the outcomes to 2 sets of controls i) sensitised patients who were waitlisted and then subsequently received a deceased donor transplant and ii) waitlisted patients who didn’t receive a transplant. For each recipient there were 5 matched controls. patients.  Controls had similar levels of panel reactive antibody as well as other factors that are known to effect graft outcome including age, blood group, diabetes, RRT prior to transplant, previous transplants etc. The levels of HLA antibody were classified as i) low (positive luminex assay but negative flow-cytometric crossmatch) ii) moderate (positive flow-cytometric crossmatch but negative cytotoxic crossmatch (CDC) and iii) high (positive CDC).
 
At 8 years patients who had received an HLAi transplant from a live donor had a survival of 76.5% versus 62.9% for the waiting list/deceased-donor transplant group versus 43.9% for the waiting list only group (p<0.001). Interestingly  this benefit held across all levels of donor specific antibody ( i.e. no matter how strong the crossmatch). So those with low levels of anti HLA antibody (as defined above) who underwent HLAi live transplant had 89.2 survival at 8 years compared to 65% (in the waitlist/deceased-donor transplant group) and 47% (in the waitlist only group). Even in the high donor specific antibody group ( i.e those with a positive CDC)  survival at 8 years was 71% versus 61.5%(p=0.004) and 43.7% (p<0.001) in the control groups. A sensitivity analysis showed there was no ‘centre effect’ suggesting that outcomes were comparable even in centres that did relatively small numbers of HLAi transplants. The survival benefits of transplantation were seen from 1 month in the low donor specific antibody group (i.e. positive luminex but negative flow cytometric crossmatch). Unsurprisingly the benefits of live donor HLAi transplantation were seen at a later time point in the high donor specific antibody ( i.e. positive CDC)  group occurring at 4.8 months ( when compared to those who remained on the waiting list) and 21.7 months (when compared to those who remained on waiting list or received a deceased donor transplant).
So what does this tell us - i) dialysis is always a high risk option for patients with end stage kidney disease as outcomes are so much worse than transplantation - whether they are diabetic, obese, or at immunological risk. This needs to be borne in mind when making treatment decisions about listing and transplantation in such patients 
ii) the results of of the CDC positive group ( traditionally considered as an absolute barrier to transplantation) were surprisingly good though clearly there is significant ‘early’ graft loss will be a problem for patients and their clinicians
iii) clearly we need more information about what treatment protocols work best ( rituximab, plasma exchange , botezomib etc).
 
However what is clear is that HLAi live donor transplantation is deliverable, delivers significant survival advantage compared to patients staying on dialysis (which is what happens to most of such patients) and as the authors suggest can be done in clinical settings other than a single-centre, high volume, specialised centre.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Monday, 14 March 2016, 3:34 PM
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I received this letter from a US Nephrologist working in non fee for service environment...

revealing!

Hello Professor Meguid El Nahas, 

I saw your article in Jama from August 2015, regarding CKD staging, 
http://jama.jamanetwork.com/article.aspx?articleid=2300875

I am a practicing nephrologist in Baltimore, MD, and I practice with Kaiser, in a non fee for service environment.  I feel like the diangosis of elderly CKD pts has gotten out of control.  CKD staging was developed as an epidemiologic tool that has turned into clinical practice, and very badly.  Telling an 85 yo female, who have about 1% chance of reaching ESRD in the their lifetime that they have stage 3 CKD , is awful and unnecessary.  In fact, telling pts they have stage 3 anything, is legitimately criminal when they have little increased risk of actually needing intervention in their lifetime.  

To this end I wanted to propose a new CKD staging system that would be more pt centric:

CKI Stage 0 - GFR > 60, with some structural abn or proteinuria 
CKI stage I - GFR 45-60 mild kidney impairment 
CKI stage II - GFR 30-45 mod kidney  impairment 
CKI stage III - GFR 15- 30  severe kidney impairment 
CKI stage IV - GFR 0 -15  kidney failure

Modifier: 
a - < 1 gm proteinuria
b - 1-3 gm proteinuria 
c - > 3 gm proteinuria 

For pts with no change to GFR by MDRD
1.  It is unlikely will be getting rid of MDRD in the near future, and now it is commonly reported with all labs. Pt get anxious when they see an abnormality in their labs. 
2.  Pts with known significant proteinuria, or structural defects, i.e. PKD, pts don't need another diagnosis of CKD.  GIving them a secondary diagnosis like IgA nephropathy and stage 1 CKD does not change their diagnosis or their prognosis, and is only useful from an epidemologic standpoint. for which CKI Stage 0 can be used. 

This model was conceived based on patient centric care, instead of epidemiology. 
The changes  have many pt centric benefits, 
1.  We stop calling patients with low GFR diseased, which is hard to justify that 30% of the adult population over 70 should be described. 
2.  When a lab is reported as abn. low GFR, this will be able to tell pts they have a mild impairment,  which is much more relieving to hear than stage 3 kidney disease.   And enough for pts to remember and dose meds accordingly. 
3.  Informing pts on stage 3 CKD , the first questions, are: what happened to stage I and 2, why wasn't I informed then? Other than explaining the complex epidemiology that led to this staging system, and that's just the way it is, there is no good reason for this.  
4.  It closely matches a 4 stage system, which patients are more familiar with, in regards to cancer staging. Stage 3  actually means something.   

I am not sure what to do with this now, as many colleagues work in a fee for service model, and seem to need the referral base, but I feel like it is ethically wrong that we have created an epidemic of kidney disease where none existed.  We have given a diagnosis to age, and the repercussions are unclear.   I would like to propose this model to someone in academics, and since I saw your article, felt you might be able to guide me in the right direction.  

Thank you for your time, 

Atif K. Jensen
  Dept of Nephrology, Towson
  office 410.339.5508 

This message implies that the notion of  "Epidemic of CKD" is linked to financial incentives for fee for service Nephrologists in the USA who aim to increase their referral basis on the back of medicalising the aging of the older population with age-related reduced kidney function and GFR...

Medicine and Money are not compatible bed fellows....

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Wednesday, 2 March 2016, 12:04 PM
Anyone in the world
Kidney Int. 2015 Nov;88(5):1161-9. doi: 10.1038/ki.2015.234. Epub 2015 Jul 29.

National trends in acute kidney injury requiring dialysis in England between 1998 and 2013.

Acute kidney injury (AKI) severe enough to require dialysis is increasing and associated with high mortality, yet robust information about temporal epidemiology of AKI requiring dialysis in England is lacking. In this retrospective observational study of the Hospital Episode Statistics (HES) data set covering the entire English National Health Service, we identified all patients with a diagnosis of AKI requiring dialysis between 1998 and 2013. This incidence increased from 774 cases (15.9 per million people) in 1998-1999 to 11,164 cases (208.7 per million people) in 2012-2013. The unadjusted in-hospital case-fatality was 30.3% in 1998-2003 and 30.2% in 2003-2008, but significantly increased to 41.1% in 2008-2013. Compared with 2003-2008, the multivariable adjusted odds ratio for death was higher in 1998-2003 at 1.20 (95% CI: 1.10-1.30) and in 2008-2013 at 1.13 (1.07-1.18). Charlson comorbidity scores of more than five (odds ratio 2.35; 95% CI: 2.20-2.51) and emergency admissions (2.46 (2.32-2.61) had higher odds for death. The odds for death decreased in patients over 85 years from 4.83 (3.04-7.67) in 1998-2003 to 2.19 (1.99-2.41) in 2008-2013. AKI in secondary diagnosis and in other diagnoses codes had higher odds for death compared with AKI in primary diagnosis code in all three periods. Thus, the incidence of AKI requiring dialysis has increased progressively over 15 years in England. Improvement in case-fatality in 2003-2008 has not been sustained in the last 5 years.

COMMENT:

An increased trend of AKI has been observed in the UK over the last 15 years. The ageing of the population and increasing co-morbidities have to be contributing factors. 

Of note the sharp in increase in AKI between 2004-2008. So we have to ask ourselves what happened in the UK during that time that may explain the sudden, and it is a sudden surge in 2006-2008 in the number of cases of AKI.

2003: KDOQI: CKD Classification

2004-5: eGFR reporting in the UK NHS and associated increase in RAAS prescribing. THis was observed in other countries worldwide. http://www.ncbi.nlm.nih.gov/pubmed/22437415

2004: Introduction of Quality and Outcomes Framework (QOF) to General Practitioners in the UK, encouraging to detect "CKD" and prescribe ACE inhibitors and other Renin Angiotensin Aldosterone System (RAAS) blockers. In fact, they get renumerated and increase their income if they prescribe ACE inhibitors...

2006: Onward surge in numbers of cases of AKI in the UK...

Is that a coincidence?!

Or is the rise in AKI in the UK the direct consequence of the inappropriate and increased prescribing of these potentially nephrotoxic agents?

In one study, up to 15% of the increase in AKI admissions in England over a 4-year time period (2007-2010) could be traced and attribued to increased prescribing of ACE-I and ARBs. http://www.ncbi.nlm.nih.gov/pubmed/24223154

The authors of the above report on AKI national trends in the UK are questioning what needs to be done to prevent further rise in AKI,

The answer is simple:

1. Educate GP to stop the indiscriminate prescribing of RAAS blockers to older people with co-morbidities including those with T2DM

2. Stop rewarding GPs in the UK for prescribing potentially nephrotoxic agents such as ACE inhibitors to the older population with comorbidities and vascular pathologies including CKD due to ischemic nephropathy

3. Educate Non-Nephrologists to the potential nephrotoxicity of RAAS blockers more specifically amongst the older population

4. Improve the understanding of CKD in the elderly; a mere reduction in eGFR that is age-related in most and inconsequential...that doesnt warrant RAAS blockade! In fact recent evidence suggest that aggressive BP control in this age group increases the incidence of both AKI and CKD: http://www.ncbi.nlm.nih.gov/pubmed/26551272

5. In fact, stopping RAAS blockers in this age group may be protective!:
http://www.ncbi.nlm.nih.gov/pubmed/19820248

6. Declassify many older patients from the label of "CKD" by a more age-sensitive CKD classification: http://www.ncbi.nlm.nih.gov/pubmed/26023760

7. Stop treating microalbuminuria in the older population with RAAS blockers; it is merely a reflection of age-related vascular disease. 

8. Debunk the myth that early treatment of CKD prevents late complications...in fact, the number needed to treat (NNT) with a RAAS blocker in those with early CKD (3a), in the absence of proteinuria, is 2,500 to prevent 1 case of ESRD...and NNT in those with CKD3a and microalbuminuria (or proteinuria = 1+) exceeds 1,000 patients treated with RAAS blockers to prevent 1 ESRD...

http://www.ncbi.nlm.nih.gov/pubmed/?term=O%27+Hare+A%2C+tamura%2C+larson%2C+batten

ALL IN ALL,

IT IS HIGH TIME TO RETHINK THE USE OF RAAS BLOCKERS IN THE OLDER GENERAL POPULATION AND IN CKD.

IT IS HIGH TIME THAT PRESCRIBING OF RAAS BLOCKERS IS CURBED AND CONTROLLED IN THE UK TO PREVENT MORE AKI AND CKD...!!!

 

  

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Meguid El Nahas - Sunday, 17 January 2016, 10:11 PM
Anyone in the world

N Engl J Med
.
 2015 Nov 26;373(22):2103-16. doi: 10.1056/NEJMoa1511939. Epub 2015 Nov 9.

A Randomized Trial of Intensive versus Standard Blood-Pressure Control.

Abstract

BACKGROUND: The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain.

METHODS: We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.

RESULTS: At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P=0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group.

CONCLUSIONS: Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062.).

 COMMENTS

Before we get carried away...and guidelines revisited...and so much more, lets stop the SPRINT...and look critically at the data:

Whilst this long awaited clinical trial showed a significant reduction in cardiovascular events in the intensive BP control group, it also reveals that intensive BP control was of no apparent benefit in patients suffering from CKD and even potentially harmful in such high risk of CVD patients.

Of note, in SPRINT intensive BP reduction did not impact on:

Cororonary artery events 

or

Cerebrovascular accidents

It improved CHF, presumably due to more aggressive diuretic therapy use in the intensive BP group...at a cost...

In CKD patients, a quarter of all those enrolled in the SPRINT trial, intensive BP control led to:

1. No reduction in CVD event rate or related mortality

2. No impact on CKD progression

3. Increased incidence of CKD

4. Increased incidence of AKI

In other words, intensive BP control led to harm in those elderly patients with or without CKD as far as  renal function is concerned.

A number of clinical trials previously showed that intensive BP control was of little benefit in non-proteinuric CKD:

REIN2 study was negative: 

http://www.ncbi.nlm.nih.gov/pubmed/15766995

AASK was also negative:

http://www.ncbi.nlm.nih.gov/pubmed/?term=intensive+BP+control%2C+Appel

the latter RCT hinted that progression may benefit of tighter BP control in those with CKD and proteinuria, an impression previously reported in the MDRD trial.

With the above in mind, Nephrologists should be cautious of overzealous BP reduction, in elderly individuals with CKD in the absence of significant proteinuria. Whilst there is no evidence of benefit, there is growing evidence of harm in the presence of hypotension in such age group. Not only faster CKD progression but also increased susceptility to AKI

(specially when the dreaded RAAS inhiobitors are used: http://www.ncbi.nlm.nih.gov/pubmed/24223154) 

and ultimately, falls and fractures known to be associated with increased morbidity and mortality in this age group.

 

 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Arif Khwaja - Friday, 4 December 2015, 3:49 PM
Anyone in the world

The evidence base for managing IgA Nephropathy has been poor based on small studies with variable control groups and standard of care. Until now KDIGO recommends aggressive ACEi/ARB therapy with a blood pressure target of 125/75mmHg. Immunosuppression with corticosteroids is recommended in patients with an eGFR >50mls/min who still have greater than 1g/24 hours of proteinuria - This is a 2C recommendation based on RCTs by Pozzi, Praga, Manno and Lv. However one criticism of these studies is that RAS inhibitors were either not part of standard care in the study or they were stopped and then restarted at baseline.

This week finally sees the publication of the STOP-IgA Nephropathy Study from Germany in the NEJM which is a game changer in clarifying the role of immunosuppression in IgA nephropathy.

In essence 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 diet. Interestingly the protocol dictated that ACEi/ARBs were titrated upto the maximum tolerable dose in patients with significant proteinuria even if BP well controlled. After 6 months those with greater than 0.75g/24 hours of proteinuria (but less than 3.5gm/24hrs) were randomised to continuing supportive care or immunosuppressive therapy - this consisted of:

i) steroids (pulsed methylprednisolone 1g for 3 days on months 1,3,5 and 0.5mg/kg every 48 hours on all other days) for 6 months for those with a GFR>60mls/min/1.73m2 or

ii) cyclophosphamide (1.5mg/kg) and steroids (40mg/day tapered to 7.5mg at month 7) for patients with an eGFR between with 30-59mls/min. After 3 months cyclophosphamide was switched to Azathioprine with prednisolone and azathioprine continued for 3 years). 

The two primary endpoints were:

i) clinical remission (defined as a PCR<0.2 and a decline in eGFR <5mls/min/1.73m2 from baseline to the end of 3 years) and

ii) a decrease in eGFR <15mls/min/1.73m2. There were a range of secondary endpoints including eGFR decline >30mls/min, proteinuria,  reciprocal creatinine slopes, proteinuria and onset of ESRD.

309 patients completed the run-in phase with 109 responding to supportive care whilst 165 still had >0.75g/24 hours of proteinuria and these patients were randomized to continue best supportive care or start immunosuppression. The groups were well matched at baseline with respect to eGFR (around 57-61mls/min/1.73m2), proteinuria (around 1.6-1.8g/24 hours) and BP (around 125/75) and virtually all patients were on ACEi and ARBs. 80 patients were randomized to supportive care whilst 82 to immunosuppression – of these 55 patients had an eGFR>60mls/min/1.73m2 and so received steroids only whilst 27 received steroids+Cyclophosphamide/Azathioprine as their eGFR was between 30-59mls/min/1.73m2.

5% of patients in the immunosuppression group achieved clinical remission versus 17% of those in standard care group (p<0.01). However this difference was driven by differences in complete remission of proteinuria and importantly there were NO differences in eGFR at 3 years. Furthermore whilst the immunosuppression arm had lower mean proteinuria at 1 year there was no significant difference at 3 years. As regards the other primary endpoint of eGFR decline >15mls/min/1.73m2 there was no difference between the two groups. Importantly 25% of patients had this degree of significant decline in kidney function. Similarly other endpoints such as eGFR/reciprocal creatinine change were not affected by immunosuppression – i.e. immunosuppression had no  impact on any measure of progression or proteinuria at 3 years.  Microhaematuria was more likely to resolve in the immunosuppression group.

Importantly immunosuppression was associated with a much higher rate of sepsis and glucose intolerance

My immediate thoughts:

i) A really important, excellent, well designed study – Professor Floege and the rest of his co-investigators in Germany must be rightly proud to be actually able to deliver such a study.

ii) The 6 month run-in period that allowed all patients to have that standard care optimized was crucial part of the study design in ensuring patients were well matched at baseline – a problem which has blighted earlier studies in IgA nephropathy. In fact the positive results of steroids in earlier studies could almost be completely explained by this failure in standardizing care. The eGFR decline in this study was 1.6mls/min/year in the supportive arm group – which was much lower than that seen in earlier studies. Furthermore the fact that nearly 1/3 of patients went into remission in this period highlights the importance of basic care – ACEi/ARB, aggressive BP control, salt restriction, lipid management and smoking control.

iii) There is clearly NO role for immunosuppression in patients with IgA nephropathy with proteinuria  less than 3.5g/day. I assume KDIGO will change its recommendation about steroids in IgA nephropathy soon. …

iv) Although proteinuria is a very powerful predictor of progression this study is an important reminder that it’s a surrogate endpoint…the higher proteinuria remission rate in the immunosuppression group did not translate into any differences in progression at 3 years…

v) Limitations  – (these are well described by the authors though I personally don’t think these are significant to change the take-home message of the study) – 3 year follow up, open label study and failure to measure GFR – however the latter is probably not significant as if anything steroids will lower muscle mass - and therefore lower creatinine and increase eGFR) - finally it may not be applicable to the non-caucasian population given the difference patterns of IgA in different ethnicities

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Friday, 27 November 2015, 5:52 PM
Anyone in the world

Lancet Diabetes Endocrinol. 2015 Oct 21. pii: S2213-8587(15)00368-X. doi: 10.1016/S2213-8587(15)00368-X. [Epub ahead of print]
Ramipril versus placebo in kidney transplant patients with proteinuria: a multicentre, double-blind, randomised controlled trial.
Knoll GA1, Fergusson D2, Chassé M3, Hebert P4, Wells G3, Tibbles LA5, Treleaven D6, Holland D7, White C7, Muirhead N8, Cantarovich M9, Paquet M10, Kiberd B11, Gourishankar S12, Shapiro J13, Prasad R14, Cole E15, Pilmore H16, Cronin V17, Hogan D3, Ramsay T3, Gill J18.

Abstract
BACKGROUND:
Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of end-stage renal disease and death in non-transplant patients with proteinuria. We examined whether ramipril would have a similar beneficial effect on important clinical outcomes in kidney transplant recipients with proteinuria.
METHODS:
In this double-blind, placebo-controlled, randomised trial, conducted at 14 centres in Canada and New Zealand, we enrolled adult renal transplant recipients at least 3-months post-transplant with an estimated glomerular filtration rate (GFR) of 20 mL/min/1·73m2 or greater and proteinuria 0·2 g per day or greater and randomly assigned them to receive either ramipril (5 mg orally twice daily) or placebo for up to 4 years. Patients completing the final 4-year study visit were invited to participate in a trial extension phase. Treatment was assigned by centrally generated randomisation with permuted variable blocks of 2 and 4, stratified by centre and estimated GFR (above or below 40 mL/min/1·73 m2). The primary outcome was a composite consisting of doubling of serum creatinine, end-stage renal disease, or death in the intention-to-treat population. The principal secondary outcome was the change in measured GFR. We ascertained whether any component of the primary outcome had occurred
at each study visit (1 month and 6 months post-randomisation, then every 6 months thereafter). This trial is registered with ISRCTN, number 78129473.
FINDINGS:
Between Aug 23, 2006, and March 28, 2012, 213 patients were randomised. 109 were allocated to placebo and 104 were allocated to ramipril, of whom 109 patients in the placebo group and 103 patients in the ramipril group were analysed and the trial is now complete. The intention to treat population (placebo n=109, ramipril n=103) was used for the primary analysis and the trial extension phase analysis. The primary outcome occurred in 19 (17%) of 109 patients in the placebo group and 14 (14%) of 103 patients in the ramipril group (hazard ratio 0·76 [95% CI 0·38-1·51]; absolute risk difference -3·8% [95% CI -13·6 to 6·1]). With extended follow-up (mean 48 months), the primary outcome occurred in 27 patients (25%) in the placebo group and 25 (24%) patients in the ramipril group (HR 0·96 [95% CI 0·55-1·65]); absolute risk difference: -0·5% (95% CI -12·0 to 11·1). There was no significant difference in the rate of measured GFR decline between the two groups (mean difference per 6-month interval: -0·16 mL/min/1·73m2 (SE 0·24); p=0·49). 14 (14%) of patients died in the ramipril group and 11 (10%) in the placebo group, but the difference between groups was not statistically significant (HR 1·45 [95% CI 0·66 to 3·21]). Adverse events were more common in the ramipril group (39 [38%]) than in the placebo group (24 [22%]; p=0·02).
INTERPRETATION:
Treatment with ramipril compared with placebo did not lead to a significant reduction in doubling of serum creatinine, end-stage renal disease, or death in kidney transplant recipients with proteinuria. These results do not support the use of angiotensin-converting enzyme inhibitors with the goal of improving clinical outcomes in this population.

COMMENT:

In this high risk group of allograft recipients , with single hyperfiltering kidneys, hypertension and proteinuria, and who are at high cardiovascular risk:

RAAS blockade with an ACE inhibitor had no advantage over other antihypertensive agents in terms of rate of decline of kidney function and mortality.

This is one of the very few studies of ACE inhibition in CKD where GFR is measured. In fact, it is the only that is reasonably powered to answer the question whether these agents have a true advantage in slowing CKD progression. The REIN study studied measured GFR in a small number of patients thus raising doubts about its power and sample size.

http://www.ncbi.nlm.nih.gov/pubmed/9217756

Other studies relied on eGFR with the possibility that ACE inhibition may affect tubular secretion of creatinine, thus lowering serum Cr and improving eGFR without any true change in Glomerular Filtration Rate (GFR).

http://www.ncbi.nlm.nih.gov/pubmed/15882297

This study confirmed the lack of different outcome in terms of changes in serum creatinine estimation (doubling) by measuring GFR thus ascertaining the true lack of specific impact of ACE inhibition with Ramipril of renal function in this high risk group: single kidney, proteinuric and high CVD.

It substantiates a number of recent observations including a systematic analysis showing no advantage of this class of drugs on outcomes.

http://www.ncbi.nlm.nih.gov/pubmed/?term=BP+lowering+trialist%2C+BMJ+2013

Time may have at last come when well conducted RCTs demonstrate that, as long as BP is well controlled, there are no added advantages for ACE inhibitors (RAS blockade) over other antihypertensive drugs!?

It took 15 years for,

FACTS: well conducted RCTs and Analysis

to catch up with

FICTION: that ACE inhibitors had an added and specific benefit above good BP control

http://www.ncbi.nlm.nih.gov/pubmed/10754405

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Friday, 27 November 2015, 5:50 PM
Anyone in the world

Lancet Diabetes Endocrinol. 2015 Oct 21. pii: S2213-8587(15)00368-X. doi: 10.1016/S2213-8587(15)00368-X. [Epub ahead of print]
Ramipril versus placebo in kidney transplant patients with proteinuria: a multicentre, double-blind, randomised controlled trial.
Knoll GA1, Fergusson D2, Chassé M3, Hebert P4, Wells G3, Tibbles LA5, Treleaven D6, Holland D7, White C7, Muirhead N8, Cantarovich M9, Paquet M10, Kiberd B11, Gourishankar S12, Shapiro J13, Prasad R14, Cole E15, Pilmore H16, Cronin V17, Hogan D3, Ramsay T3, Gill J18.

Abstract
BACKGROUND:
Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of end-stage renal disease and death in non-transplant patients with proteinuria. We examined whether ramipril would have a similar beneficial effect on important clinical outcomes in kidney transplant recipients with proteinuria.
METHODS:
In this double-blind, placebo-controlled, randomised trial, conducted at 14 centres in Canada and New Zealand, we enrolled adult renal transplant recipients at least 3-months post-transplant with an estimated glomerular filtration rate (GFR) of 20 mL/min/1·73m2 or greater and proteinuria 0·2 g per day or greater and randomly assigned them to receive either ramipril (5 mg orally twice daily) or placebo for up to 4 years. Patients completing the final 4-year study visit were invited to participate in a trial extension phase. Treatment was assigned by centrally generated randomisation with permuted variable blocks of 2 and 4, stratified by centre and estimated GFR (above or below 40 mL/min/1·73 m2). The primary outcome was a composite consisting of doubling of serum creatinine, end-stage renal disease, or death in the intention-to-treat population. The principal secondary outcome was the change in measured GFR. We ascertained whether any component of the primary outcome had occurred
at each study visit (1 month and 6 months post-randomisation, then every 6 months thereafter). This trial is registered with ISRCTN, number 78129473.
FINDINGS:
Between Aug 23, 2006, and March 28, 2012, 213 patients were randomised. 109 were allocated to placebo and 104 were allocated to ramipril, of whom 109 patients in the placebo group and 103 patients in the ramipril group were analysed and the trial is now complete. The intention to treat population (placebo n=109, ramipril n=103) was used for the primary analysis and the trial extension phase analysis. The primary outcome occurred in 19 (17%) of 109 patients in the placebo group and 14 (14%) of 103 patients in the ramipril group (hazard ratio 0·76 [95% CI 0·38-1·51]; absolute risk difference -3·8% [95% CI -13·6 to 6·1]). With extended follow-up (mean 48 months), the primary outcome occurred in 27 patients (25%) in the placebo group and 25 (24%) patients in the ramipril group (HR 0·96 [95% CI 0·55-1·65]); absolute risk difference: -0·5% (95% CI -12·0 to 11·1). There was no significant difference in the rate of measured GFR decline between the two groups (mean difference per 6-month interval: -0·16 mL/min/1·73m2 (SE 0·24); p=0·49). 14 (14%) of patients died in the ramipril group and 11 (10%) in the placebo group, but the difference between groups was not statistically significant (HR 1·45 [95% CI 0·66 to 3·21]). Adverse events were more common in the ramipril group (39 [38%]) than in the placebo group (24 [22%]; p=0·02).
INTERPRETATION:
Treatment with ramipril compared with placebo did not lead to a significant reduction in doubling of serum creatinine, end-stage renal disease, or death in kidney transplant recipients with proteinuria. These results do not support the use of angiotensin-converting enzyme inhibitors with the goal of improving clinical outcomes in this population.

COMMENT:

In this high risk group of allograft recipients , with single hyperfiltering kidneys, hypertension and proteinuria, and who are at high cardiovascular risk:

RAAS blockade with an ACE inhibitor had no advantage over other antihypertensive agents in terms of rate of decline of kidney function and mortality.

This is one of the very few studies of ACE inhibition in CKD where GFR is measured. In fact, it is the only that is reasonably powered to answer the question whether these agents have a true advantage in slowing CKD progression. The REIN study studied measured GFR in a small number of patients thus raising doubts about its power and sample size.

http://www.ncbi.nlm.nih.gov/pubmed/9217756

Other studies relied on eGFR with the possibility that ACE inhibition may affect tubular secretion of creatinine, thus lowering serum Cr and improving eGFR without any true change in Glomerular Filtration Rate (GFR).

http://www.ncbi.nlm.nih.gov/pubmed/15882297

This study confirmed the lack of different outcome in terms of changes in serum creatinine estimation (doubling) by measuring GFR thus ascertaining the true lack of specific impact of ACE inhibition with Ramipril of renal function in this high risk group: single kidney, proteinuric and high CVD.

It substantiates a number of recent observations including a systematic analysis showing no advantage of this class of drugs on outcomes.

http://www.ncbi.nlm.nih.gov/pubmed/?term=BP+lowering+trialist%2C+BMJ+2013

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Picture of Meguid El Nahas
by Meguid El Nahas - Friday, 27 November 2015, 5:50 PM
Anyone in the world

Lancet Diabetes Endocrinol. 2015 Oct 21. pii: S2213-8587(15)00368-X. doi: 10.1016/S2213-8587(15)00368-X. [Epub ahead of print]
Ramipril versus placebo in kidney transplant patients with proteinuria: a multicentre, double-blind, randomised controlled trial.
Knoll GA1, Fergusson D2, Chassé M3, Hebert P4, Wells G3, Tibbles LA5, Treleaven D6, Holland D7, White C7, Muirhead N8, Cantarovich M9, Paquet M10, Kiberd B11, Gourishankar S12, Shapiro J13, Prasad R14, Cole E15, Pilmore H16, Cronin V17, Hogan D3, Ramsay T3, Gill J18.

Abstract
BACKGROUND:
Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of end-stage renal disease and death in non-transplant patients with proteinuria. We examined whether ramipril would have a similar beneficial effect on important clinical outcomes in kidney transplant recipients with proteinuria.
METHODS:
In this double-blind, placebo-controlled, randomised trial, conducted at 14 centres in Canada and New Zealand, we enrolled adult renal transplant recipients at least 3-months post-transplant with an estimated glomerular filtration rate (GFR) of 20 mL/min/1·73m2 or greater and proteinuria 0·2 g per day or greater and randomly assigned them to receive either ramipril (5 mg orally twice daily) or placebo for up to 4 years. Patients completing the final 4-year study visit were invited to participate in a trial extension phase. Treatment was assigned by centrally generated randomisation with permuted variable blocks of 2 and 4, stratified by centre and estimated GFR (above or below 40 mL/min/1·73 m2). The primary outcome was a composite consisting of doubling of serum creatinine, end-stage renal disease, or death in the intention-to-treat population. The principal secondary outcome was the change in measured GFR. We ascertained whether any component of the primary outcome had occurred
at each study visit (1 month and 6 months post-randomisation, then every 6 months thereafter). This trial is registered with ISRCTN, number 78129473.
FINDINGS:
Between Aug 23, 2006, and March 28, 2012, 213 patients were randomised. 109 were allocated to placebo and 104 were allocated to ramipril, of whom 109 patients in the placebo group and 103 patients in the ramipril group were analysed and the trial is now complete. The intention to treat population (placebo n=109, ramipril n=103) was used for the primary analysis and the trial extension phase analysis. The primary outcome occurred in 19 (17%) of 109 patients in the placebo group and 14 (14%) of 103 patients in the ramipril group (hazard ratio 0·76 [95% CI 0·38-1·51]; absolute risk difference -3·8% [95% CI -13·6 to 6·1]). With extended follow-up (mean 48 months), the primary outcome occurred in 27 patients (25%) in the placebo group and 25 (24%) patients in the ramipril group (HR 0·96 [95% CI 0·55-1·65]); absolute risk difference: -0·5% (95% CI -12·0 to 11·1). There was no significant difference in the rate of measured GFR decline between the two groups (mean difference per 6-month interval: -0·16 mL/min/1·73m2 (SE 0·24); p=0·49). 14 (14%) of patients died in the ramipril group and 11 (10%) in the placebo group, but the difference between groups was not statistically significant (HR 1·45 [95% CI 0·66 to 3·21]). Adverse events were more common in the ramipril group (39 [38%]) than in the placebo group (24 [22%]; p=0·02).
INTERPRETATION:
Treatment with ramipril compared with placebo did not lead to a significant reduction in doubling of serum creatinine, end-stage renal disease, or death in kidney transplant recipients with proteinuria. These results do not support the use of angiotensin-converting enzyme inhibitors with the goal of improving clinical outcomes in this population.

COMMENT:

In this high risk group of allograft recipients , with single hyperfiltering kidneys, hypertension and proteinuria, and who are at high cardiovascular risk:

RAAS blockade with an ACE inhibitor had no advantage over other antihypertensive agents in terms of rate of decline of kidney function and mortality.

This is one of the very few studies of ACE inhibition in CKD where GFR is measured. In fact, it is the only that is reasonably powered to answer the question whether these agents have a true advantage in slowing CKD progression. The REIN study studied measured GFR in a small number of patients thus raising doubts about its power and sample size.

http://www.ncbi.nlm.nih.gov/pubmed/9217756

Other studies relied on eGFR with the possibility that ACE inhibition may affect tubular secretion of creatinine, thus lowering serum Cr and improving eGFR without any true change in Glomerular Filtration Rate (GFR).

http://www.ncbi.nlm.nih.gov/pubmed/15882297

This study confirmed the lack of different outcome in terms of changes in serum creatinine estimation (doubling) by measuring GFR thus ascertaining the true lack of specific impact of ACE inhibition with Ramipril of renal function in this high risk group: single kidney, proteinuric and high CVD.

It substantiates a number of recent observations including a systematic analysis showing no advantage of this class of drugs on outcomes.

http://www.ncbi.nlm.nih.gov/pubmed/?term=BP+lowering+trialist%2C+BMJ+2013

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world
N Engl J Med. 2015 Sep 17. [Epub ahead of print]

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

Abstract

Background The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. Methods We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. Results A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. Conclusions Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676 .).

 COMMENTS

Inhibitors of SGLT2 (sodium-glucose cotransporter-2) inhibitors are hypoglycemic agents that have shown benefit in the management of heart failure in their capacity as potent osmotic diuretic effect through increased glycosuria.

In this study, Zinman et al show a benefit in all cause and cardiovascular mortality in patients at high cardiovascular risk due to T2DM.

It is intriguing that the only difference related to CVD outcomes, in this study, is heart failure; all other causes of CVD death such as myocardial infarctions or strokes dont seem different in those on SGLT2 inhibitors and placebos.

The only difference between the two groups seem to depend on a significant reduction in heart failure, related hospitalisation and death.

This, along with a reduction in weight and BP in the SGLT2 inhibitors treated group, implies that the beneficial effect is primarily related to the diuretic effect of this agent. Unfortunately, the placebo group did not incorporate additional diuretic therapy to match that of the two SGLT2 inhibitors arms.

The questions that warrant consideration is:

Is this agent worth precribing for its protective effect on CVD death due to heart failure in its capacity as an expense diuretic...?

notwithstanding its considerable potential side effects including urosepsis (fourfold higher in this study in those treated with SGLT2 inhibitors compared to placebo), genital candidiasis, and even urogenital malignancies...

not to mention and undoubted higher cost that diuretics such as chlorthalidone known to be protective in patients at high CVD risk as shown in the ALLHAT study?

http://www.ncbi.nlm.nih.gov/pubmed/10789664

Also, in this high risk group of patients with high CVD risk who are often on ACE inhibitors, and who often suffer from CKD, is there an increased risk of AKI associated with the use of excessive SGLT2 inhibition-induced excessive diuresis?

Whilst the authors make optimistic mechanistic claims, I remain unconvinced that the reported benefit is no more than one due to optimisation of diuresis and management of hypervolemia and fluid retention causing heart failure.

Is Empaglifozin, an expensice Chlorthalidone?!

 

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
Anyone in the world
N Engl J Med. 2015 Sep 17. [Epub ahead of print]

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

Abstract

Background The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. Methods We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. Results A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. Conclusions Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676 .).

 COMMENTS

Inhibitors of SGLT2 (sodium-glucose cotransporter-2) inhibitors are hypoglycemic agents that have shown benefit in the management of heart failure in their capacity as potent osmotic diuretic through increased glycosuria.

In this study, Zinman et al show a benefit in all cause and cardiovascular mortality in patients at high cardiovascular risk due to T2DM.

It is intriguing that the only difference related to CVD ouitcomes is heart failure; all other causes of CVD death such as myocardial infractions or stokes dont seem different in those on SGLT2 inhibitors and placebos.

The only difference between the two groups seem to depend on a significant reduction in heart failure, related hsopitalisation and death.

This along with a reduction in weight and BP in the SGLT2 treated group that the beneficial effect is primarily related to the diuretic effect of this agent. Unfortunately, the placebo group did not incorporate additional diuretic therapy to match that of the two SGLT2 inhibitors arms.

The questions that warrant consideration is:

Is this agent with its protective effect on CVD death due to heart failure an expense diuretic...with considerable potential side effects including urosepsis (fourfold higher in this study in those treated with SGLT2 inhibitors compared to placebo), genital candidiasis, and even urogenital malignancies...and high cost, worth its use!?

Also, in this high risk group of patients with high CVD risk who are often on ACE inhibitors, is there an increased risk of AKI associated with the uise of excessive SGLT2 inhibition-induced diuresis?

 

 

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