Urine Neutrophil Gelatinase-Associated Lipocalin and Risk of Cardiovascular Disease and Death in CKD: Results From the Chronic Renal Insufficiency Cohort (CRIC) Study.
Chronic kidney disease is common and is associated with increased cardiovascular disease risk. Currently, markers of renal tubular injury are not used routinely to describe kidney health and little is known about the risk of cardiovascular events and death associated with these biomarkers independent of glomerular filtration-based markers (such as serum creatinine or albuminuria).
Cohort study, CRIC (Chronic Renal Insufficiency Cohort) Study.
SETTING & PARTICIPANTS:
3,386 participants with estimated glomerular filtration rate of 20 to 70mL/min/1.73m2 enrolled from June 2003 through August 2008.
Urine neutrophil gelatinase-associated lipocalin (NGAL) concentration.
Adjudicated heart failure event, ischemic atherosclerotic event (myocardial infarction, ischemic stroke, or peripheral artery disease), and death through March 2011.
Urine NGAL measured at baseline with a 2-step assay using chemiluminescent microparticle immunoassay technology on an ARCHITECT i2000SR (Abbott Laboratories).
There were 428 heart failure events (during 16,383 person-years of follow-up), 361 ischemic atherosclerotic events (during 16,584 person-years of follow-up), and 522 deaths (during 18,214 person-years of follow-up). In Cox regression models adjusted for estimated glomerular filtration rate, albuminuria, demographics, traditional cardiovascular disease risk factors, and cardiac medications, higher urine NGAL levels remained associated independently with ischemic atherosclerotic events (adjusted HR for the highest [>49.5ng/mL] vs lowest [≤6.9ng/mL] quintile, 1.83 [95% CI, 1.20-2.81]; HR per 0.1-unit increase in log urine NGAL, 1.012 [95% CI, 1.001-1.023]), but not heart failure events or deaths.
Urine NGAL was measured only once.
Among patients with chronic kidney disease, urine levels of NGAL, a marker of renal tubular injury, were associated independently with future ischemic atherosclerotic events, but not with heart failure events or deaths.
Copyright © 2014 National Kidney Foundation, Inc. All rights reserved.
What seems to be overlooked by one track Nephrologists and CKD aficonados is that HNAG/Lipocalin has many sources other than the renal tubules including neutrophils known to be a risch source of NGAL and involved in atherosclerosis.
In fact, leukocytosis and a high neutrophil count is alo a risk factor for CVD along with a number of neutrophils release products:
This is also the case for monocytes/monocytosis like releasers of NGAL:
So NEPHROLOGISTS need to take their blinkers off and realise that NGAL, like previous factors before, thought to be relased from a single cell or organ, are pleomorphic factors almost universally released by numerous cells within the body...
Remember Vitamin D and its 1alpha hydroxylation..thought for generations to be unique to the kidney and noiw found to take place in numerous extra-renal cells...
Sio regardless of the kidney, its injury or otherwise, inflammatory markers including Leukocytosis, ESR, CRP, hiyerfibrogenemia, etc...and raised NGLA...are all predictors of CVD and CAD.
BMJ 2014;349:g5448 doi: 10.1136/bmj.g5448 (Published 4 September 2014)
How guidelines can fail us
Fiona Godlee editor in chief, The BMJ
Should patients be offered β blockers if they have ischaemic
heart disease and are about to undergo high risk surgery?
Guidelines from the European Society of Cardiology say that
they should, citing evidence that it prevents perioperative
myocardial infarction. Others are unconvinced and say that the
recommendation should be revoked. Initially set at class 1, the
strongest level, the recommendation was retained in 2011 even
though key randomised trials were discredited. In the most
recent update of the guidance, published last month, the
recommendation still stands, albeit at class IIb.
How does this stack up against the remaining trial evidence? A
meta-analysis published in 2013, which excluded the discredited
trials, found that perioperative β blockade in patients at risk was
harmful, associated with a statistically and clinically significant
increase in mortality. And the authors of that meta-analysis,
writing this week in The BMJ (2014;349:g5210, doi:10.1136/
bmj.g5210), tell a strange and unsettling story of subsequent
events, one that is hard to reconcile with the treasured belief
that medicine servesthe best interests of patients and the public.
Those of us who thought we had seen an end to guidelines drawn
up among vested interests behind closed doors will be
disappointed. In Graham Cole and Darrel Francis’s account, we
hear of a secrecy agreementsigned by the guideline authorsthat
is so secret that even its existence must be kept secret. Where
is the openness on which science depends? We hear of
guidelines being led by the authors of the major trials—in this
case the very trialsthat turned out to have corrupted the evidence
base. Where is the scope for critique of researchers who are in
positions of power? We hear of what I would consider to be too
close a relationship between the society and its journal. Where
is the space for dissenting voices?
I will be interested to know whether readers share the authors’
clear disquiet about distorted priorities. When the series of
randomised trials was discredited and the senior author, Don
Poldermans, dismissed from his post, the European Society of
Cardiology’s statement concluded, “We are saddened by Prof
Poldermans’ situation.” Cole and Francis in contrast saw more
to be sad about in the patients who may have died as a result of
guidelinesthat were based on falsified and fictitious data. Using
the discredited research group’s own formula, they calculated
that the number of iatrogenic deaths might have reached 800
000, with half of those occurring after the research had been
discredited. This estimate, with caveats and cautions, was
published in the society’s journal, the European Heart Journal,
but the article was almost immediately removed. A substantially
revised version, without the estimate of deaths, is apparently
due for publication, but the original article is published as an
appendix to the article in The BMJ this week.
Let me quote from it: “Professional failure in clinical research
is not uncommon. If readers are not watching carefully, journals
are not listening seriously, and guideline writers are not free to
act swiftly, future failures may again risk enduring harm with
global reach. The aviation profession hasled the way in systems
to prevent, recognize,study, and learn from professional failures.
Clinical medicine is now following the same path. We must
develop similar systems for research.”
Cite this as: BMJ 2014;349:g5448
Another sobering account of Publications, Meta-analyses, Key opinion Leaders, Guidelines, Guideline panels, and Big Pharma...
Discerning doctors, Nephrologists and readers of publications and Guidelines have to take more responsibility by critically appraise what is dished out for them...to ultimately protect themselves from malpractice...and their patients from the consquences...Claiming ignorance and blind faith in the published word...can kill!
Prediction of membranous nephropathy recurrence after transplantation by monitoring of anti-PLA2R1 (M-type phospholipase A2 receptor) autoantibodies: a case series of 15 patients.
The predictive value of anti-M-type phospholipase A2 receptor (PLA2R1) autoantibodies for membranous nephropathy (MN) recurrence after renal transplantation remains controversial.
Our aim was to monitor anti-PLA2R1 IgG4 activity using a sensitive enzyme-linked immunosorbent assay in 15 kidney transplant recipients with MN, and to test the correlation between antibody titres and MN recurrence.
Five patients never exhibited anti-PLA2R1 antibodies, and one of them relapsed. Ten patients (67%) had IgG4 anti-PLA2R1 antibodies at the time of transplantation and during follow-up. The presence of IgG4 anti-PLA2R1 antibodies at the time of kidney transplantation does not imply MN recurrence (P = 0.600, n = 15). However, a positive IgG4 anti-PLA2R1 activity during follow-up (>Month 6) was a significant risk factor for MN relapse (P = 0.0048, n = 10). Indeed, four patients had persistent IgG4 anti-PLA2R1 activity after transplantation and relapsed. Among them, one was successfully treated with rituximab. Another had persistently high IgG4 anti-PLA2R1 activity and exhibited a histological relapse but no proteinuria while on treatment with renin-angiotensin system inhibitors. In contrast, the six other patients who did not relapse exhibited a decrease of their IgG4 anti-PLA2R1 activity following transplant immunosuppression, including two with proteinuria due to biopsy-proven differential diagnoses. A weak transplant immunosuppressive regimen was also a risk factor of MN recurrence (P = 0.0048, n = 10). Indeed, the six patients who received both an induction therapy and a combined treatment with calcineurin inhibitors/mycophenolate exhibited a decrease of IgG4 anti-PLA2R1 activity and did not relapse, while the four patients who did not receive this strong immunosuppressive treatment association had persistently high IgG4 anti-PLA2R1 activity and relapsed.
The monitoring of IgG4 anti-PLA2R1 titres during follow-up helps to predict MN recurrence, and a strong immunosuppressive treatment of anti-PLA2R1 positive patients may prevent recurrence.
This very interesting observation adds to the evolving knowledge related to IMN and the pathogenic role of anti-PLA2R1 autoantibody.
It encourages the practice of screening potential transplant recipient with a history of IMN for anti-PLA2R1, as the titres of this autoantibody prior to transplantation may guide the immunosuppressive regimen used not only to induce successful induction of tolerability of the allograft but also to suppress anti-PLA2R1 titre, thus preventing, or at least decreasing the risk, of IMN recurrence in the allograft.
A similar approach has been advocated for approaching renal transplantation in aptients with FSGS at higher risk of recurrence in the allograft where screening for, and possibly monitoring, suPAR (soluble urokinase-type plasminogen activator receptor) levels may guide management.
Finally, it would be interesting to know if allograft ischemia and DGF, or even ACR, were associated with a higher incidence of IMN recurrence as damage to the allograft podocytes may expose the antigenic epitopes that trigger the re-emergence of anti-PLA2R1 and the subsequent IMN.
As to the management of the patients who have recurrent IMN with high circulating titres of anti-PLA2R1, a previous report suggested a good response to Rituximab (anti-CD20) therapy, with decreased proteinuria, stabilisation of allograft function and disappearance of the autoantibody.
SHARP Study GRoup.
The SHARP study group showed in their original publication that lipids lowering with a combination of simvastatin and ezetimibe had little effect on overall or cardiovascular mortality in CKD.
They also showed that lipid lowering had no effect on CKD progression.
Now, it seems as if the SHARP study group has embraked on republisihng these findings individually.
In this month JASN (August 2014), a paper entitled:
Effects of lowering LDL cholesterol on progression of kidney disease...NO EFFECT.
But this is a duplicated result to that published in the original SHARP report!?
I am suprised that top quality journals dont preclude publication duplications.
I expect to see over th enext few months more SHARP Publications:
Lipids lowering on CAD: NIL....
Lipids lowering on Overall Strokes incidence: NIL....
Lipids lowering on Non-Cardiovascular Mortality....NIL
Lipids Lowering on Cardiovascular Mortality...NIL
MANY PAPERS IN PROSPCET FOR THE SHARP COLLABORATIVE GROUP...
VERY LITTLE NEW INFORMATION IN STORE FOR THE NEPHROLOGISTS...!
It strikes that Nephrologists are so keen to publish theat they often publish short term, incomplete, underpowered and inaccurate informations...that shape our practice.
Two recent examples, in ANCA associated systemic vasculitis (AASV):
We wre told, by teh authors of the MEPEX trial, that plasma exchange improves outcomes in AASV that is associated with advanced renal insufficiency or dialysis dependent at presentation; this was based on a 12months, underpowered study with numerous shortcomings and flaws.
THIS BECAME STANDARD PRACTICE WORLDWIDE...
Now we are told, by the same authors, in a larger study with a longer follow-up:
"...Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV...."
IN OTHER WORDS, NO EVIDENCE THAT PLASMA EXCHANGE MAKES ANY DIFFERENCE ON PATIENTS SURVIVAL OR EVEN DIALYSIS DEPENDENCY...
Another example, from the same group of experts (EUVAS), has taught us many moons ago that in AASV maintenance therapy with Azathioprine was a good and less side effecst that cyclophopsphamide and we should switch ar 3 months after remission has been induced: CYCAZAREM study.
THIS BECAME STANDARD PRACTICE WORLDWIDE...
Now teh same authors are telling us that perhaps after all that is not the case and switching to azathioprine at 3 months may not be recommended...:
" ...It remains uncertain whether converting to azathioprine after 3-6 months of induction cyclophosphamide therapy is as effective as converting after 12 months. Outcomes are still poor for this group of patients and further research is required to determine the optimal timing of maintenance therapy...."
IN OTHER WORDS, THEY DONT KNOW....
These examples, and previous ones, I remember all too well the recommendations of Aspirin + Dipyridamole for mesangiocapillary glomerulonephritis and improved survival over 12 months...only to be proved ineffective over 3 years (Donadio et al in the 80s)...., highlight a number of trends:
1. Over eagerness to publish before being sure of the facts...
2 Publication is more important to some that patients' care...
3. Better publish a poorly documented and incomplete piece of research than wait for the more comprehensive and thorough evaluation of a given intervention...
ULTIMATELY, IT IS US JOBBING NEPHROLOGISTS WHO ARE MISLED...BUT MORE SERIOUSLY, IT IS OUR PATIENTS THAT PAY THE COST OF HASTE...AND SHORT TERMISM....
Two articles have been published this month in the NEJM relating to the PURE study outcomes:
N Engl J Med. 2014 Aug 14;371(7):601-11. doi: 10.1056/NEJMoa1311989.
N Engl J Med. 2014 Aug 14;371(7):612-23. doi: 10.1056/NEJMoa1311889.
The FIRST PUBLICATION, showed that a high urinary excretion of sodium correlates, in a large population (>100,000) in 18 countries worldwide, with systolic and diastolic blood pressure (BP). The slope of the association was steeper for those with hypertension and in older age (>55 years).
An inverse relationship was noted with high urinary potassium excretion.
SO FAR SO GOOD, SO A HIGH URINARY SODIUM EXCRETION = A HIGH SODIUM INTAKE IS ASSOCIATED IN THOSE AT HIGHER RISK WITH A RISE IN BP. THIS ALL THE WAY AS FAR AS SODIUM EXCRETION TO <3G/DAY.
THE SECOND PUBLICATION, showed that a urinary sodium excretion/intake of <3g and >6g/day is associated with increased CARDIOVASCULAR EVENTS. In this study, low <3g/day and high >6g/day sodium intake was associated with increased CVD events. Those individuals between 3 and 6g/day of sodium intake had the lowest CVD. Thus defining a U shape curve with increased risk at high and low sodium intake levels.
In fact, such J/U shaped curve also goes along a similar curve profile for BP and in that respect does not contradict the first study; low BP like High BP are associated with increased mortality. High BP leads to increased risk of CVD and low may reflect the presence of severe CVD and heart failure, specially in the elderly.
Similarly, high sodium/salt intake is associated with high BP and increased CVD whilst low sodium intake may reflect poor health, poor food intake also reflecting an underlying higher comorbidity.
SO WHERE'S THE CONFUSION?
The confusion emanates from such observations (implying that a low sodium/salt intake may be potentially harmful) and current BP guidelines and recommendations including those for CKD patients that advise to reduce the sodium intake of patients to <2g/day:
Thus leaving us in a confused state:
Is lower sodium intake beneficial?
Is lower sodium intake harmful?
Is lower sodium intake beneficial in some age group; >55 years and/or hypertensive?
Is lower sodium intake harmful/unncessary in some age groups <55years and/or normotensive?
Which brings us back to guidelines and healthcare management in general that has to be tailored and adjusted to the individual under consideration as data derived from cross sectional observational studeis like PURE are at best hypothesis generating and not convincing facts we can build our practice upon.
So perhaps we would only be confused if we surrender our own common sense and judgement and apply guidelines an drecommendations blindly...
ONE SIZE NEVER FITS ALL IN MEDICINE...THIS IS HIGHLIGHTED IN REGARDS TO SODIUM INTAKE AS WELL AS BLOOD PRESSURE LEVELS AND CONTROL.
AGE AND COMORBIDITIES HAVE TO BE TAKEN INTO CONSIDERATION WHEN WE MAKE OUR OWN CLINICAL DECISIONS....MORE SALT IN SOME...LESS SALT IN OTHERS...PURE-LY CONVINCING!
So the SHARP study is also negative as far as the impact of STATINS ON CKD PROGRESSION...as it is on other major outcomes such as hospitalisations and mortality in CKD.
YET...IT IS OVERALL SPAN AS A STUDY THAT SHOWED THAT STATINS REDUCED MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) IN CKD PATIENTS....
THIS IS TOTALLY MISLEADING...AS:
SHARP FAILED TO SHOW ANY IMPACT OF STATINS ON:
1. All cause mortality
2. Vacsular/CVD Mortality
3. Non Vascular mortality
5. CAD and its complications
6. Strokes of unknown causes
AND NOW...as previously suggested CKD AND ITS PROGRESSION.
SO WHY IS SHARP SPUN TO NEPHROLOGISTS AS A POSITIVE STUDY THAT REDUCES CVD?
AND WHY DO NEPHROLOGISTS BELEIVE SUCH SPIN?
1. Clearly many Nephrologists are gullible...
2. Many Nephrologists dont know how to read a publication/report critically...
3. Most Nephrologists know little about statistical analyses...
4. Those with a vested interest in a study positive outcomes, including BIG PHARMA, are smart...and take advantage of our shortcomings and fool us to beleive in what is in their interest...
Based upon the fact that SHARP showed BY THE INAPPROPRIATE USE OF SOFT ENDPOINTS AND COMPOSITE ENDPOINTS:
a. A reduction in THE SOFT ENDPOINT OF vascular revascularisation; a procedure freely and subjectively undertaken in many countries, including the USA, by interventionists with little justification, indications or lasting beneficial outcome. In favour of such assumption is the absence of any IMPACT of statins on harder CAD endpoints such as myocardial infarction or coronary related mortality...!!!???
b. A Reduction in ischemic/non-hemorragic strokes; whilst other strokes were not affected AND more significanlty the hard endpoint of death from ischemic strokes is NOT affeceted...!!!!
Also to bare in mind, STATINS INCREASE THE INCIDENCE OF HEMORRHAGIC STROKES as shown in numerous studies including AURORA but also in the recent analysis of the Framingham Heart Study (FRS) where statins increased the risk of cerebral bleeds...
c. SHARP innapropriately used COMPOSITE ENDPOINTS, mixing meaningful and irrelevant outcomes in order to rely on the meaningless (revascularisation procedures) to give the impression that the meaningful MACE are improved on Statins...WRONG AND MISLEADING and a poor and ill informed use of composite endpoint in clinical trials:
In fact, there is a complete disconnect in SHARP between the chosen soft endpoints coronoray revascularisations and ischemic stroke events and the HARD ENDPOINTS related to these such as hospitalisations or MORTALITY....?!
ALTOGETHER SHARP IS A NEGATIVE STUDY SHOWING NO MEANINGFUL EFFECT OF STATINS ON HOSPITALISATIONS OR ANY TYPE OF MORTALITY IN CKD PATIENTS....IT IS BEING SPUN TO CONVINCE US OTHERWISE...SO BEWARE...AS SUCH SPIN HAS ALREADY FOOLED MANY INCLUDING THE KEY OPINION LEADERS WHO DRAFT NATIONAL AND INTERNATIONAL GUIDELINES...BUT IT SHOULDNT FOOL YOU!
I have been practicing Medicine and Nephrology for 40 years.
It occured to me that true and major breakthroughs in the management of CKD have been few and far between during these 40-50 years.
In fact, when I started practicing Nephrology and until recently CKD meant: Glomerulonephritis, Pyelonephritis, Reflux nephropathy and Dysplastic Kidney Disease (later called CAKUT), Hypertensive nephrosclewrosis, diabetic nephropathy and PKD (ADPKD).
CKD in the community, with its "epidemic" and all that is the brainchild of KDOQI and KDIGO CKD definitions and classifications that have created a monster out of the decline in kidney function in the over 50 and 60 years...This I will not comment upon here as I have already on many occasions only to dismiss this community CKD (cCKD) and all its ills as the takeover by epidemiologists (rather biostatisticians) and the ones I call "Spreadsheet Nephrologists" of our beautiful profession and specialty...
Back to true Nephrology, and true CKD (previously called Chronic renal failure [CRF]), no biostatistians or epidemiologists needed to tell us that its incidence and prevalence have somewhat increased due to ageing and the associated increase in hypertension and DM - related CKD. Also, more and more elderly present with atherosclerotic and ischemic nephropathies.
But my point here is:
40 years on, has there been any major therapeutic breakthrough in the management of true referred CKD (rCKD)?
My answer is NO:
1. When I started we had a range of anti-hypertensive agents including diuretics and beta-blockers. They treat hypertension effectively with a few other classes of agents including RAAS inhibitors. What matters is the BP control regardless of the agent or class of agents used.
2. For GN primary or secondary, we had immunosuppression with steroids +/- azathioprine/cyclophosphamide. Steroids and Azathioprine/cyclophosphamide remain the cornerstone of the management of GN.
3. For Reflux nephropathy/Pyelonephritis, we had antibiotics prophylactically or otherwise, we still have them, although the clever bacteria we treat or trying to prevent have learned to become more resistant...
3. For ADPKD, still the same treatment, early diagnosis and treatment of hypertension.
4. For HT nephrosclerosis, control hypertension and nil else...
5. For DN, control hypertension and not much more...
So little therapeutic advances that proved superior to those we used 40 years ago...in spite of almost 40-50 years on unabated research and promises to slow CKD progression:
Anti-platelets, anticoagulants, prostaglandins manipulations, nitric oxide manipulations, cytokines, chemokines and growth factors antagonsists, not to mention a number of anti-fibrotic strategies including pirfenidone, collagen synthesis and deposition inhibition etc...and of course TGF-beta1 remains the most fibrogenic of growth factors...and we still have not managed to translate that knowledge (20 years old by now) to the bedside...???!!!
Very disappointing...and worth questioning whether the R&D as well as translation strategies we are relying upon to discover new and more effective therapies to slow CKD progression are effective or at least cost-effective?
May be thats why Nephrologists started to look elsewhere, came up with a new definition of CKD, created new detection tools (eGFR formulas), teamed up with biostatisticians, screened everybody, generated a "CKD Epidemic" to give themselves a new impetus and generate more attention to their dormant specialty...?!
The 3C study presented at this weeks’ World Transplant Congress and published online in the Lancet is an important study, which may in the future inform clinical practice in transplantation. In essence there are two parts to the study. The first part looks at induction therapy and compares induction with alemtuzumab (and anti-CD52 monoclonal antibody that depletes mature lymphocytes and is licensed for the treatment of multiple sclerosis and CLL) vs basiliximab – an IL2- receptor antagonist. Those randomised to alemtuzumab also received tacrolimus (targeting a lower therapeutic 5-7 ng/ml) and low dose mychphenolic acid (MPA 360mg bd) but no steroids. In contrast those randomised to basiliximab received steroids, higher dose tacrolimus (5-12ng/ml) and higher dose MPA (540mg bd). The second part of the study looks at switching patients 6 months post transplant from tacrolimus to sirolimus or continuing tacrolimus.
The data presented this week is very early data from the induction part of the study and looks at the impact of a standard basiliximab-based regime vs the steroid-free alemtuzumab-based regime with lower-dose tacrolimus and MPA on biopsy proven acute rejection (BPAR) at 6 months. Groups were well matched though on the whole were of low immunological risk – 92% were first transplants and 4% highly sensitised
The key findings are as follows:
i) There was a significant, 58% proportional reduction in BPAR in the alemtuzumab group (7% of patients) vs the Basiliximab group (16% of patients). Graft function at 6 months was the same in both groups.
ii) The reduction in BPAR was driven by a significant reduction in early cellular rejection. Antibody mediated rejection incidence was 1.9% in the alemtuzumab group but 1.2 % in in the basiliximab group – this was non significant.
iii) There was no difference in CMV viraemia, CMV disease and other opportunistic infections between both groups but BK viraemia was significantly higher in the alemtuzumab group (8% vs 4%). There was no difference in the number of serious infections or hospitalisations
iv) 11 patients died in the alemtuzumab arm compared to 6 in the basiliximab arm. This was not statistically significant but perhaps a little concerning.
v) Leucopaenia was much commoner in the alemtuzumab group – 36% vs 10%.
Like many other clinicians in the UK I have consented patients into the study. To me the interesting points so far are:
i) the 3C study represents a huge success for the UK transplant community in general but in particular for the Oxford Clinical Trials Unit that ran the study. To have recruited so many patients into a study in a relatively short period of time is incredibly difficult and happened because clinicians up and down the country ‘bought’ into the study and the trials unit made it logistically as easy as possible for all investigators
ii) The data is broadly in line with the results of the previous INTAC study which showed that alemtuzumab reduced BPAR in low risk transplant recipients compared to basiliximab whilst enabling an early steroid taper.
iii) The authors emphasise in the discussion that reducing BPAR does not necessarily translate into better graft survival. However the study is powered to detect long-term outcomes and this data will come out in a few years time and we will then be in a position to determine the impact of alemtuzumab induction is on more meaningful outcomes than BPAR.
iv) The results do suggest alemtuzumab-induction does allow for the delivery of steroid-free immunosuppression regimes using lower doses of MPA and tacrolimus – albeit in relatively low risk transplant recipients
v) Although infection rates were broadly similar the ‘big hassle’ of the patients randomised to alemtuzumab was leucopenia which affected a third of patients. There maybe scope to attenuate this by introducing MPA a little later once the lymphocyte count recovers or using a lower dose of alemtuzumab.
vi) Previous retrospective data suggests that alemtuzumab use is associated with an increased risk of antibody-mediated rejection. In the previous INTAC study late acute rejection occurred in 10% of patients in the high-risk group on alemtuzumab vs 2% in the ATG group. Whilst not statistically significant such a difference is worrying. The longer term 3C data will hopefully be able to tease out whether this risk of late rejection (perhaps associated with repopulation of lymphocytes) is a real concern.
In summary the data presented so far are interesting and may clarify a role for alemtuzumab in the delivery of steroid-free immunosuppression once the longer-term outcome data is presented.
This month in the Lancet:
An editorial by Farhat Yaqub on:
Rana Dajani and teh Ethics of Stem cell Research in the Middle East.
The editorial highlights Dr Rana Dajani elevated position in medical and biology research with emphasis on her work in genetics but also the potential of stem cell research to treat many genetic and rare diseases.
Dr Dajani who works at the Hashemite University in Jordan has initiated working and advisroy partiers to explore the potential of stem cell research therapy in medicine and has involved physicians, scientists but also religious and legal experts.
This is a very important step forward in the ethics and governance of medical research in the Middle East and in aprticular in research and potential treatment involving stem cells.
Stem cell therapies like all medical innovcative interventions require considerable governance to translate from basic science to the bedside. Whilst such governance and guidance are often in palce in high economies, the translation of medical adsvances into clinical practice often lacks rigorous governance and good clinical practice (GCP) in emerging countries.
All too often patirents are treated with experiemntal intyerventions before such GCP related steps are implemented and even before ethical and IRB approval or even consideration. This has to be subject of grave concern as patients with geentic conditions, those with orphan and rare disease and others with a range of metabolic abnormalities potentially amenable to stem cell therapies have to be protected against malpractices before they benefit from good practices...
They need to be protected from:
1. being used as guineapigs for greedy scientists and investigators
2. being exploited, and their suffering, by money seeking investigators, physicians and Pharma.
3. being exposed to potential risks before benefiting from potential advances.
4. being duped to beleive their are treated with proven interventions...whe in reality they are subject of research into unproven interventions...after all that is the essence of clinical trials: to Test and Unproven intervention that seems promisiiong...as if it was of proven benefit, it would no longer be ethical to deny its benefits from a control group given placebo....
5. being subjects in poorly controlled and badly conducted "clinical research" that ultimately will yeild no meaningful outcome other than boost the income of the sponsors and investigators of such research...
More than in any other field of medicine, stem cell researchj and therapy has raised considerable hopes and expectations amongst the medical profession and those suffering from a wide range of diseases from Daibetes mellitus, heart failure, multiple sclerosis to spinal injury and kidney diseases, but the road ahead is long....and in emerging countries the risk of exploitation is high, thats why the work of people like Rana Dajani has to be commented and followed with great interest.
This Blog aims to raise awareness of the importance of Good Clionical Practice and the Governance and Ethics of Medical Research in Emerging countries;
IT IS NOT ALWAYS AS GOOD AND ETHICAL AS WE WOULD EXPECT...
In this field, as in many others, conflicts of interest between researchers, physicians and Industry is a threat to research and advances integrity. Tight policies have to be in place to safeguard medical practice and patients.
In this field, examples are common of abuse and malpractices that dont live up to ethical or moral expectations:
In this field of stem cells, less regulation may be warranted for basic research but more regulation has to be implemented acroos the board with special attention to emerging countries when it comes to teh translation of basci scientific advances to the bedside and patients' care:
FINALLY WE NEED TO GUARD OURSELVES AND OUR PROFESSION AGAINST USING PATIENTS HOPES AND EXPECTATIONS, TO GENERATE UNWARRANTED HYPE THAT AIMS TO PROMOTE THOSE WHO USE THE POTENTIAL NEW THERAPIES, SUCH AS STEM CELLS, IN UNETHICAL AND IMMOARL WAYS: