User blog: Arif Khwaja
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.
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
Despite the plethora of publications regarding kidney transplantation outcomes, immunosuppression remains remarkable similar in most centres. CNIs (usually tacrolimus), anti-metabolites (usually) MMF and steroids with IL2-receptor antagonism remaining the cornerstone of immunosuppression for most transplant centres. Of course there are variations on this (some centres maybe steroid free, others may use ATG induction) but broadly speaking graft outcomes are similar across most large transplant centres. Consequently there have been few interventions that have made any difference to graft outcomes in that last 10 years. Recently there has been increasing interest in donor interventions than can impact on graft outcomes - e.g. machine perfusion of kidneys from deceased donors has been shown to reduce delayed graft function (DGF -defined as the need for dialysis within the week after transplant) and possibly improve allograft function at one year.
In this weeks NEJM, Niemann and colleagues publish data looking at the effect of therapeutic hypothermia in patients transplanted in California and Nevada. In essence donors who had been declared brain dead according to neurological criteria were randomised to two target temperatures: hypothermia (34-35 C) or normothermia (36.5-37.5 C). Hypothermia was achieved either by not actively warming patients or through the use of ‘forced air-systems or passive cooling devices’ ( there is no further detail on what this actually is in practice).
The headline figures show that the trial was terminated early after the independent safety board saw a clear benefit of induced hypothermia. A total of 572 patients received a kidney from 370 donors. DGF developed in 28% of the hypothermia group and 39% of normothermia group - there was a significant difference (p=0.02). This was based on a multivariable analysis that accounted for variables that can influence DGF such as donor type (expanded vs standard-criteria), donor creatinine and age and cold ischaemia time. The beneficial effect of hypothermia was particularly striking in the expanded criteria donors (adjusted odds ratio 0.31;CI 0.15-0.68; p=0.003) whereas in the standard criteria group although hypothermia reduced DGF this did not reach statistical significance. The authors reasonably conclude that this may reflect the benefit of hypothermia is via mitigation of ischaemia-reperfusion injury.
As well as normothermia other statistically significant factors assocaied with an increased risk of DGF included donor age, cold ischaemia time, donor creatinine and donor age.
A few things worth pointing out. As the investigators could not control all donor variables it is worth noting that the cold ischaemia time in the hypothermia group was slightly (but significantly) less than in the normothermia group. This may of course skew the data in favour of hypothermia but it was accounted for in the multi-variate analysis. Furthermore although there were no safety signals, no long term data is presented so we don’t know whether this reduction in DGF translates into graft function at 1 year or any other longterm meaninful outcome. Finally there is little information presented on how hypothermia was achieved so I’m not quite clear how costly such an intervention would be.
In summary this is a really interesting study that suggests a relatively safe and presumably easy to deliver intervention (hypothermia) can have a meaningful impact graft outcomes particular in kidneys from expanded criteria donors. It will be interesting to see how quickly this intervention is taken up by the broader transplant community
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.
A quick update from the late clinical trials session from the ERA-EDTA which was a high quality session
A few months ago I saw an 82 year old lady with very slowly progressive CKD4. She had T2DM, hypertension, a strong history of smoking and was referred by her GP as she had an eGFR of 29 mls/min ( compared to 35 mls/min 5 years ago). Her US showed slightly small kidneys and her dipstick was negative for protein and blood and immunology screen was negative. She was assumed to have ischaemic nephropathy as the cause of her CKD. She had been taking NSAIDs for 20 years for arthritis
Her BP was 152/90 and she was reasonably well - she lived independently with some support from her daughter. When I saw her her main problem was her arthritis - this was severe and she was racked with pain particularly in the morning. The nephrologist who saw her on her prevoius visit had understandbly told her to stop taking NSAIDs ( Ibuprofen 200mg tds) and instructed her family doctor to increase her anti-hypertensive medications by adding in a diuretic
The problems were two fold i) she couldnt tolerate other pain killers ( nausea, constipation and hallucinations) so she was left taking paracetamol which didnt work. ii) She was already on a number of vasodialtors which left her with significant oedema and as she had an overactive, small bladder she found that taking diuretics meant that going out was difficult and so now had to stay at home as she was afraid of being incontinent in public.
What struck when me I saw here was that two very reasonable (from a nephrologists perspective) interventions (ie. stopping NSAIDs and increasing anti-hypertensive medication) had significantly worsened the quality of her life.... which got me thinking what was the actual 'value' we were adding to her quality of life or life expectancy by seeing her? Perhaps they were the following:
i) Reducing her risk of developing ESRD? This ladys risk of developing ESRD in her lifetime is miniscule.. as shown in the GLOMMS study women of this age with no albuminuria virtually never progress to ESRD and so if our goal is to try and reduce the risk of her developing ESRD then we are trying to reduce the risk of someting that is vanishingly unlikely to happen - even if she never sees a nephrologist. This was further brilliantly highlighted in a recent publication extrapolating the effect of a putative intervention that reduces the risk of ESRD by 30% in RCT to an elderly population with CKD. The reality was that the effect would be negligible for most of the elderly as few will progress - again highlighting the importance of interpreting RCT data in the context of the patient on front of you
ii) Stopping NSAIDs will reduce her risk of developing ESRD? Given the fact that she had been taking NSAIDs for 20 years with only a slow decline in kidney function the value of stopping NSAIDs in her case on either her life expectancy or quality of life are negligible - indeed her quality of life was significantly worse after stopping NSAIDs. So perhaps a better approach would have been to tell her to continue taking her NSAIDs (stopping only if she gets intercurrently ill) and to continue monitoring her kidney function regularly. And as a recent systematic review showed the impact of NSAIDs used at a normal dosage on GFR decline is negligible.
iii) Getting better control of her BP will reduce her risk of cardiovascular disease? Putting aside the fact that at the age of 82 with a lifetime of smoking, the dice in terms of CV risk has already been cast, would lowering lowering her blood pressure really improve her CV risk? - well there is increasing evidence that treating to a ‘target’ of less than 140/90 mmHg may not only have no benefit but may for some patients be harmful. In fact the evidence base from interventional studies to support a ‘tight’ BP target in this age group is negligible.
So what did I do…. well I stopped her diuretic, told her to go back on her NSAIDs - Her BP was 152/90 and her eGFR 30mls/min and most importantly she was now happy that she could get out of the house (without worrying about incontinence) and her pain was controlled. When I started talking about CV risk and salt in her diet, her eyes glazed, she leaned forward and said “you do know I’m 82 don’t you...?"
So what did I learn? well without sounding trite the clear learning message from this case is that treating risk is not the same as treating a patient…What matters to us ( e.g reducing proteinuria and BP, stopping NSAIDs) may not matter to the patient and whilst in some cases doing things like tightly controlling BP, reducing proteinuria and stopping NSAIDs will be incredibly important, in other situations they are at at best irrelevant and at worse counterproductive.
This balance between the ‘evidence-based medicine’ and ‘patient-centred care’ has been articulated by a thought-provoking recent article by Ann O’Hare in NDT which continues on from an earlier article stressing the importance individualised rather than disease-based care - a must read for anyone who actually practises medicine and sees real-world pateints.
In other words the certainties and value of guidelines and ‘evidence-based medicine’ are only realised if you can interpret them in the context, society, healthcare system and culture in which you practice and understand their relevance to the patient sitting in front of you. Real-life clinical medicine is still an art - a balance of risks, uncertainties, trade-offs and compromises.
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.
High impact journals tend to focus on clinical trial data that are likely to impact on practice. So it was nice to see a very simple but elegant piece of ‘bench to bedside’ work published in this weeks’ NEJM from Canaud and colleagues from INSERM, Paris looking at the role of mammalian target of rapamycin (mTOR)signalling in the pathogenesis of proliferative vascular lesions and fibrosis in patients with in patients with Anti-Phospholipid Syndrome (APS). APS is characterised not only recurrent thrombosis but also by proliferation of vascular smooth muscle cells and fibrosis of the vascular intima and media. i.e. vasculopathy exists in APS even in the absence of significant thrombosis.
mTOR is a serine/threonine protein kinase that belongs to the PI3-Kinase family that integrates a variety of intracellular and extracellular signalling pathways that control cell metabolism, growth, proliferation and survival. mTOR is the catalytic subunit of 2 distinct complexes mTORC1 and mTORC2 that localise to distinct subcellular compartments and have differing biological function. Inhibitors of mTOR such as sirolimus or everolimus are widely used in kidney transplantation and there is increasing interest in their use in polycystic kidney disease and general organ fibrosis. Of course their anti-proliferative, anti-fibrotic effects in kidney transplantation manifest clinically as impaired wound healing but potentially beneficial effects on tumours such as skin cancer. Similarly sirolimus eluting coronary stents have been shown to inhibit recurrent vascular stenosis and therefore the group hypothesized that mTORC pathway may be involved in the lesions in APS.
They looked at 35 patients with APS (25 of whom had lupus) who had undergone kidney transplantation and compared with 74 case-controls. Immunohistochemistry and immunofluorescence for phosphorylated S6 ribosomal protein (S6RP – a marker of mTORC1 activity) and phosphorylated Akt (a marker of mTORC2 activity) provided an assay of mTORC activity in kidney biopsies. Colocalisation experiments were also performed using markers of endothelial cells and vascular smooth muscle cells.
The key findings were:
i) significantly increased activation of both mTORCs in endothelial cells and vascular smooth muscle cells from patients who had APS- nephropathy – there was also increased proliferation of both endothelial and vascular smooth muscle cells in kidney biopsies
ii) Anti-phospholipid antibodies isolated from serum from patients with APS markedly upregulated mTORC1 and mTORC2 in a human endothelial cell line (HMEC-1 cells) and this activation was abolished by preincubation of cells with mTOR inhibitors including sirolimus. This upregulation did not appear to be due to anti-HLA antibodies as these antibodies were equally prevalent in the control patients who did not have evidence of increased mTORC activity. Control human IgG did not upregulate mTORC activity.
iii)Biopsies performed at 3 and 12 months after transplantation revealed markedly increased phosphorylation of S6RP and AKT (i.e. increased mTORC activity) in APL patients compared to controls. Furthermore APL patients on Sirolimus had significantly reduced evidence of mTORC activation compared to those APL patients not on sirolimus and this was associated with a significant reduction in the development of vascular lesions on biopsy (as characterised and quantified by fibrous intimal hyperplasia)
iv) The improved vascular histology in APS patients on sirolimus was associated with better graft survival and eGFR post-transplantation compared to those APS patients not on sirolimus – although the numbers are very small. All patients with APS were anticoagulated
The biopsy staining as well as the in vitro data with anti-phospholipid antibodies from patient sera suggest that the vascular lesions in APS post-transplantation are mediated by activation of mTORC by antiphospholipid antibodies. One has to be careful about making clinical recommendations on the basis of this kind of work but the data does seem to suggest that sirolimus maybe a better agent than a CNI for APS patients post-transplant. Whilst there are clearly lots of questions about delineating the precise mechanism of how anti-phospholipid antibodies activate mTORC and how this translates into a particular histological phenotype, the work presented is a very elegant example of applying basic science to better understand a clinico-pathological phenotype.
In the last few weeks I've received 2 contrasting emails from the UK Renal Association (RA) and the International Society of Nephrology both concerning the appointments of people to various positions in each respective society. The RA approach is very simple - any member can stand for any position and is elected by a simple electronic and postal ballot. In other words one member one vote and all the key positions are usually elected.
In contrast the process for the selection of the president elect of the ISN seems much more opaque. I can nominate somebody, but the nominations are scrutinised by the 'nominations committee' to ensure that the candidate fits in with the 'ISN mission, mindset and spirit.' After that the process to me as an ordinary member isnt clear - but as far as I can tell a shortlist of screened candidates are then voted on in a secret ballot of the ISN council - I maybe wrong on the precise mechanics here but I know one thing is clear - members of the ISN arent able to directly elect the president of the ISN on the basis of one member one vote.
Does any of this really matter? After all the ISN is a great organisation and I'm a proud member of it. For a small fee I get 2 excellent journals ( Kidney International and the brilliant Nature Nephrology Reviews) as well as access to a wealth of educational initiatives and meetings. As an example the Sister Renal Centre and the fellowship programs have been fantastic initiatives in transforming care and developing relationships around the world. I am particularly proud of of our own relationship in Sheffield with Sister Renal Centres in Bosnia and Egypt.
However going back to the process of electing the president of the ISN a few things are clear... if any member wants to change the 'mission, mindset and spirit' of the ISN they would presumably be unable to get past the nominations committee. The contrast with the RA is striking... members stand for various positions with a short statement of their manifesto i.e. what they would like to do. The membership then votes for people on the basis of their positions and whoever gets the most votes assumes the position. Its a great way of ensuring the the leadership of a society reflects the beliefs and wishes of the membership.
When I go to WCN meetings I am always struck by the huge number of people attending from all over the world - a huge mix of nationalities and ethnicities that presumably in part reflects the ISNs very diverse, international membership. Yet a quick look the 22 presidents of the ISN paints a completely different picture: 20 out the 22 presidents have been from Europe, USA and Australia. The remaining 2 were from Japan and Venezuela, both as far as I can tell had worked in the USA. There has never been a black or brown president. It is amazing that a society that is supposed to represent the international nephrology voice has never had a president from Africa, the Middle East, India or China.
Does this matter when the presidents have all clearly been people of outstanding calibre? Well yes I think it does matter - societies need to reflect their memberships and for societies to thrive they need to be actively evolving their 'mission, mindset and spirit' to meet the needs of their membership but more importantly the global needs of patients with kidney disease. Its for this reason I hope that one day we will have a president of the ISN who hasn't trained in an academic centre of excellence in North America, Europe or Australasia but somebody who has experienced a completely different clinical environment and who can thereby develop and evolve the ISN further. Diversity matters - not as a sop to political correctness - but as a way of hearing different voices and perspectives and so strenghtening and enriching organisations.
The Athenians first established a democratic process around 2500 years ago and generally the concept has been seen as pretty successful. In the 21st century maybe the ISN should start to look again at the way it chooses its' president.....
There has been much interest in the last couple of years in the potential of renal denervation to manage resistant hypertension particularly after the SYMPLICITY-HTN-2 study was published in the Lancet several years ago.
There have been a number of studies sponsored by medical device companies including SYMPLICITY and EnligHTN that have been active recently. At last we have the data with the publication of SYMPLICITY HTN-3 in the New England Journal of Medicine.
In this study patients with severe resistant hypertension (all patients were on the maximum doses of at least 3 drugs including a diuretic) were randomly assigned in a 2:1 ratio to undergo renal denervation or a sham procedure. The primary end point was change in office blood pressure (probably a poor surrogate for actual blood pressure) and a secondary endpoint including a safety composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis. A particular strength of the study was that 24 hour ambulatory BP was measured as well as office BP as a secondary endpoint and an impressive 535 patients were included in the study
The bottom line was that there was NO significant difference in the primary endpoint in both groups. Furthermore whilst blood pressure fell significantly in the denervation group it also fell in the sham group ( the mean (±SD) change in systolic blood pressure at 6 months was −14.13±23.93 mm Hg in the denervation group as compared with −11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline) with no significant differences in office BP between the groups. 24 hour ambulatory BP failed to show a positive impact of denervation either: 6.75±15.11 mm Hg fall in BP in the denervation group and −4.79±17.25 mm Hg. Again this difference was not significant.
There were no safety concerns with denervation. Subgroup analysis did not show any positive impact in any subgroup including 10% of patients with 'renal impairment'
The findings are at odds with previous studies such as the unblinded SYMPLICITY HTN-2 trial which showed significant reductions in blood pressure with denervation.
So how come the difference - well what the study highlights is the importance of blinding in a clinical trial. The positive results from earlier trials were from unblinded studies whilst in this study blood pressure fell significantly in the sham-procedure group as well... the reasons of this aren’t clear but we know that there can be a powerful 'placebo' effect in any clinical study. In medical device studies 'sham' interventions are the equivalent of the placebo or control arm - yet such sham interventions are often not performed for 'ethical' reasons of not wanting to subject patients to a sham-intervention that maybe associated with risk to the patient. Yet SYMPLICITY HTN-3 clearly demonstrates the absolute necessity for having such a sham-intervention group when evaluating the impact of medical devices. The reasons underlying the BP fall in the sham group aren’t clear but we know that being enrolled in any clinical trial often brings improvements even in the control/placebo arm. This may simply be as a result of increased contact with medical professionals resulting in improved patient adherence in medications and general good care.
Enthusiasts for denervation may say that one of the problems is that the radiologist has no 'read out' to tell them whether denervation has been successful and this may account in part for these disappointing results. However ablation catheter used in the SYMPLICITY HTN-3 study was no different from that used in the SYMPLICITY HTN-1 and HTN-2 studies.
My colleague Will McKane who has considerable expertise in denervation tells me that he has anecdotal experience of denervation being a huge success in some patients with resistant hypertension with some patients achieving good control on minimal medication after years of intractable, severe hypertension. Indeed the standard deviations indicate that there can be a very broad response to denervation and so it is possible that a positive impact of denervation in selected patients was ‘hidden’ in the mass of data from the trial. However we don’t have good evidence to support this nor is there anyway of identifying those who may respond.
As was pointed out in an accompanying editorial in NEJM there has been enormous hype around denervation with many claiming it to be a potential ‘cure’ for hypertension. That bubble has now burst and at the moment its difficult to see any significant future for denervation in the management of resistant hypertension