User blog: Arif Khwaja
The management of FSGS particularly post -transplantation remains difficult with no clear evidence base on how to optimally manage recurrent disease. The search for a permeability factor continues and recent work suggested that serum-soluble urokinase-type plasminogen activator receptor (SuPAR) may have an important role in FSGS by modulating integrin signalling within podocytes promoting foot process effacement and proteinuria. As yet there is significant variablility in SuPAR levels (and no standardised assay) in differing FSGS cohorts so its utility as a biomarker is far from certain.
There is a fascinating editorial on the 'Equity and Economics of Kidney Disease in Sub-Saharan Africa' by Luyckx and colleagues in this weeks Lancet, as part of their series focussing on kidney disease. The statistics bearing out the human/financial cost of ESRD are horrendous.
This weeks NEJM sees the publication of 2 open label, phase 2 studies describing the experience of Eculizumab in atypical HUS (aHUS). Eculizumab is a humanised monoclonal antibody that inhibits activation of complement by binding to C5 complement protein thereby preventing the generation of proinflammatory C5a and C5b-9. Eculizumab is licensed for the treatment of paroxysmal nocturnal haemoglobinuria. aHUS is characterised by chronic activation of the complement system as a result of either genetic or acquired defects. (See here for excellent review on complement and aHUS).
All patients with evidence of Shiga-toxin producing E-Coli or low ADAMTS13 activity were excluded from the 2 trials. In study 1, 17 patients were treated if they had i) evidence of progressive thrombotic microangiopathy (TMA) as determined by declining platelet count ii) haemolysis iii) evidence of abnormal kidney function ( median eGFR was 19mls/min/1.73m2 and iv) > 4 plasma exchange/infusion sessions in the week prior to screening. 15/17 patients completed treatment to 26 weeks and another 13 continued through an extension phase. The primary endpoint was change in platelet count though GFR, requirement for plasma exchange and quality of life were also recorded. There was a significant increase in platelet count with 87-88% having normal platelet counts and LDH by 26 weeks ( ie. no significant evidence of TMA and haemolysis), a significant increase in eGFR from baseline to 26 weeks by 32mls/min/1.73m2 and a significant improvement in quality of life at 26 weeks ( not surprising as disease had effectively been controlled for most subjects). 15/17 patients required no further plasma exchange
Trial 2 involved more 'chronic' aHUS patients who were being treated with plasma exchange at least once every 2 weeks (but less than 3x week) for at least 8 weeks. 80% met the primary endpoint (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) and no patients required dialysis or plasma exchange.
In both studies serious adverse events were very common some of which were thought to be drug related including severe hypertension, peritonitis and influenza. All patients received meningococcal vaccination and prophylaxis.
So what does this tell us? Clearly doing an RCT in a rare, acute and often explosive disease such as aHUS is very difficult and therefore the investigators are to be congratulated on conducting a trial in such a difficult area. The trial confirms that complement dysregulation is a central therapeutic target in aHUS. Whilst Eculizumab has significant toxicity (and the consequences of longterm use are not known), requires repeated infusions on a weekly to 2 weekly basis, aHUS itself has disastrous consequences with upto 40% dying or developing ESRD within the first year of presentation. Furthermore the drug clearly works preventing the need for long term plasma exchange and improving TMA, kidney function but also quality of life. An in vivo assay of complement activity revealed Eculizumab inhibited complement within one hour of infusion. Patients who missed doses of Eculizumab were more likely to develop severe complications of TMA.
So Eculizumab clearly represents a major step forward in the treatment of aHUS. Both the FDA and the European Medical Agency have granted a license for Eculizumab in aHUS. There is obviously huge interest in its use in other complement-mediated disease processes such as MPGN, catastrophic anti-phospholipid antibody syndrome and even antibody-mediated rejection in transplantation. However the real elephant in the room is what is cost - wikipaedia says that Eculizumab costs $600,000 USD per year. In the UK haemodialysis is roughly £30,000 ($45,000) per annum which means that it doesnt compare favourably to dialysis in terms of cost-effectiveness. It is important that research into rare diseases continues and new therapies are developed and clearly those companies that take on such risky projects need to get their 'reward' otherwise others will stop doing research in the area. However this kind of price is prohibitively expensive for most healthcare economies unless a different pricing structure and/or model of funding is developed such as 'performance-related' funding in the UK for the use of bortezomib in myeloma.
There is increasing interest in frequent haemodialysis (whether nocturnal or daily) as a result of the frequent daily dialysis study which demonstrated that frequent HD was superior to thrice weekly HD with respect to the composite endpoint of death and left ventricular mass. Its worth pointing out here that there was no significant difference in death between the two groups and its perhaps not surprising that LVMI was better in the daily dialysis group given the tighter volume control. One thing that is not mentioned as much is the higher incidence of vascular access problems in the frequent dialysis group. Now a post-hoc analysis of the two FHN trials by Daugiridas in this months Kidney International highlights some important concerns about the apparently deleterious impact of frequent hemodialysis on residual kidney function (RKF). They showed that in the Nocturnal Trial 63 patients had significant RKF at baseline. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared with 18% and 36% in controls. In contrast in the daily dialysis trial dialysis frequency did not impact on RKF - however the range of RKF was narrower in this study and patients with a Kidney urea clearance (Kru) >3 ml/min/35 liters estimated body water were excluded which thus may have limited the capacity to detect differences.
Its important not too read too much into such post-hoc analyses, that werent powered to evaluate the impact on RKF. Furthermore there are all sorts of methodological issues with how best to measure KRF as pointed out by Professo Farrington in an accompanying editorial. However notwithstanding these limitations the study raises important questions that need to be considered -
i) the increasing vogue for frequent dialysis in the literature needs to be tempered by a better understanding of the potential risks such as negative impact on RKF and vascular access. Hypotension, volume depletion, inflammation may all be mechanisms by which frequent dialysis negatively impacts on RKF.
ii) how frequent is frequent and is there a frequency of dialysis (say 4X week) which may offer the benefits of frequent dialysis without the adverse consequences? clearly we simply dont know the answer to this but like much of the nephrology there probably needs to be a paradigm shift away from uniform therapy for all ( say thrice weekly dialysis) to individualised therapy which takes into account factors such as comorbidity, likelihood of transplantation and RKF. Like many nephrologists I now have some patients on 4 -5 times a week dialysis with others and some only on twice a week dialysis. The thrice weekly standard dialysis prescription maybe suitable for many but certainly not all patients. Thus finding easier ways of measuring RKF may then allow us to individualise therapy appropriately. Trying to get timed collections of urine in patients on dialysis can be fiendishly difficult.
iii) The choice on dialysis seems to be between tight fluid and BP control (with resulting anuria) or a more 'hydrated' state with better preservation of RKF. Farrington argues that we should be trying to do both but the reality is at the moment we simply have no real idea of how to manage volume in the haemodialysis patient and what we are trying to aim for. Whilst overhydration appears to be harmful and asociated with adverse outcomes defining normohydration is not something we are able to easily do. The Tassin approach to fluid management may work in Tassin but Im not sure how translatable this is to other clinical settings and populations.Tools such as bioimpedance measurement may help but these have yet to transition from the research arena to the dialysis floor.
In the UK the growth in kidney transplantation in recent years has been predominantly fueled by both increasing live-related transplantation and increasing use of donors after circulatory death (DCDs - or what were previously known as non-heartbeating donors). Around a third of kidneys used in the UK are DCDs, but the use of DCDs has varied across centres with some being enthusiastic proponents whilst others such as being more cautious. Of course the main concerns amongst clinicians is whether such kidneys are as 'good' as kidneys donated after brain death (DBD), with concerns over the impact of anoxic, warm iscahemia time coupled with prolonged cold ischaemia on long term graft survival. A recent analysis of UK Transplant Registry data by Summers and colleagues in the Lancet sheds some light on what the outcomes are in such kidneys.
The investigators analysed 1768 DCDs and 4127 DBDs transplanted between 2005 and 2010. DCD kidneys had a higher rate of delayed graft function (DGF) than DBDs (49% vs 24%) but patient and graft survival at 3 years were no different. The 12 month eGFR (which maybe a reasonable surrogate for longer term graft survival) was significantly lower in the DCD group vs the DBD group (mean eGFR =48mls/min vs 50mls/min, p<0.04). Kidneys from donors over the age of 60 years were twice as likely to result in graft failure compared to those under the age of 40, irrespective of whether they were DBDs or DCDs.
In contrast to age, cold storage time (> 24 hours vs<12 hours) did impact adversely on graft survival in DCDs but not in DBDs. i.e. warm ischaemia seems to 'prime' the kidney for further damage resulting from prolonged cold storage. Whilst there has been promising data from a large, well conducted European RCT showing that hypothermic perfusion improves DGF, kidney function and graft survival, this study only included a small number of kidneys were DCDs. In contrast, a UK RCT study specifically evaluating machine perfusion in DCDs, showed no impact of hypothermic machine perfusion on DGF, patient and graft survival at 1 year.
What are the implications of this work?
Well firstly it can reassure clinicians and patients that short-term (i.e. 3 year) outcomes are the same for DBDs and DCDs and that in this timeframe the age of the donor rather than whether they are a DCD or DBD is what matters. Therefore increasing the use of DCDs may increase the overall donor pool and access to transplantation. The price of this maybe slightly worse graft function at 3 years and applying this registry data to individual patient-decision making in the middle of the night will always be fiendishly difficult for transplant surgeons - taking into account recipient comorbidity and age etc will remain paramount.
Secondly its clear that the cold storage time does adversely impact on outcomes of DCDs and this therefore needs to be taken into account when devising an allocation policy for DCDs. Whilst national allocation of DBDs seems sensible, national (rather than regional) allocation of DCDs with inevitable prolongation of cold storage time may simply lead to worse outcomes. This data casts considerable doubt on current deliberations in the UK to move towards a national allocation scheme for DCDs unless guarantees can be made about cold storage time.
Last year I wrote a blog outlining the results from the Dutch CONTRAST study which was a large RCT which failed to show any benefit of online-haemodiafitration (OL-HDF) when compared with haemodialysis in terms of mortality. Recently 2 further large RCTs have been published comparing OL-HDF to haemodialysis which add significantly to theevidence base about he relative merits of OL-HDF when compared to conventional HD.
Firstly, the Turkish Hemodialfiltration Study was recently published in NDT. In this RCT, 782 patients were randomised to receive either high-flux HD or OL-HDF. At 2 years there was no significant difference in survival between the two groups - 77.6% in OL-HDF versus 74.8% in the high-flux group, P = 0.28. Its worth pointing out here that here that the authors stated that 'statistical power for this analysis was lower than hypothesized during the design of the study' in part due to a lower than expected event rate in the control group. In a post-hoc analysis of those in the OL-HDF group who actually achieved substitution volumes of >17.4 litres per session there was a mind-boggling 46% reduction in overall mortality and 71% risk reduction for cardiovascular mortality when compared to high flux HD. However its worth pointing out that those in the OL-HDF group who achieved high convective volumes were less likely to be diabetic, had higher serum albumin and higher blood flow rates. Whilst this was controlled for in the analysis it is entirely possible that better survival rates in those who achieved convective volumes >17.4l were simply 'healthier' patients.
The second study is the ESHOL study sponsored by the Catalonian Society of Nephrology, which was a multicentre, RCT that randomised 906 patients to receive either OL-HDF or haemodialysis (92% of those randomised to the haemodialysis arm received high-flux HD) and has just been published in JASN. The headline figures are impressive and are in striking contrast to both the CONTRAST and the Turkish HDF studies which both failed to achieve their primary endpoints. Those assigned to OL-HDF had a 30% lower risk of all-cause mortality, a 33% lower risk of cardiovascular mortality, and a 55% lower risk of infection-related mortality. The reduction cardiovascular mortality was primarily driven by a reduction in the number of strokes. The estimated number needed to treat suggested that switching eight patients from hemodialysis to OL-HDF may prevent one annual death which suggests that OL-HDF was having an astonishing clinical impact.
So why the striking difference between the ESHOL and Dutch/Turkish studies? The answer is not obvious to me but it is worth considering the following:
i) In the ESHOL study no formal statistics are done on the baseline characteristics of each group but its worth noting that there are baseline differences between the two groups. 7.5% of the OL-HDF group dialysed via a line compared to 13.1% of the HD group. The mean age was 66.3 years in the HD group vs 64.5 years in the OL-HDF group and 22.8% of the OL-HDF group were diabetic compared to 27.1% of the HD group. The Charlson Comorbidity Index was 6 in the OL-HDF group and 7 in the HD group. What I genuinely dont understand is why there was no statistical analysis to see if these baseline differences were statistically significant. Instead these variables were included in multivariate analyses and then treatment risk estimates were calculated in all subgroups. I assume this is an accepted statistical approach but I am just left with this nagging doubt that the 55% reduction in infection related mortality in the OL-HDF group is in part related to the fact that were nearly 40% less lines in this group than in the HD group.
ii) the reduction in strokes with OL-HDF accounted for most of the reduction in cardiovascular risk and this may well have been related to the significant reduction in intradialytic hypotension that was observed in this group compared to the HD group.
iii) a consistent theme that emerges from all three studies is that that actual replacement volume delivered seems to matter. The median replacement volume in the ESHOL study was around 21 litres/session compared to 17 litres/session in the Turkish Study and around 20 litres/session in the CONTRAST study. Indeed post-hoc analyses of both the Turkish and CONTRAST studies showed higher convective volumes did associate with better survival. This was also seen in a post-hoc analysis in the ESHOL study where those with >25 litres/session of convective volume had a 45% reduction in mortality. However what isn't clear is why some patients who are randomised to OL-HDF are able to achieve high convection volumes and others aren't. In particular I wonder whether factors such as quality of access and cardiac function may somehow select out those who are able to achieve high convection volumes. Thus its plausible that those who can tolerate high volume OL-HDF are simply those with better cardiac function
iv) many will be surprised at the scale of the impact of OL-HDF in the ESHOL study. There have been so many negative RCTs in large dialysis populations it is surprising to see that simply switching 8 patients from high-flux HD to OL-HDF can prevent one death per year.. I am not sure if this is plausible particularly given the fact that most of the reduction in mortality is driven by a reduction in infections and if this is due to OL-HDF how is OL-HDF reducing the risk of infections? Furthermore I'm not sure if the scale of impact seen in ESHOL will be translated to having a similar impact in routine clinical practice. For example in the UK, the centre that has been using OL-HDF for the longest period of time is Stevenage and they published their rather impressive experience here in cJASN - yet UK Registry Data does not suggest that patients in Stevenage have better survival than other centres in the UK that don't routinely use OL-HDF
Therefore the evidence from these 3 studies is a bit mixed. ESHOL showing remarkable effects that some may think are 'too good to be true' whilst the CONTRAST and Turkish-HDF studies failing to meet their primary endpoint. If OL-HDF is to be used than the actual convective volume delivered seems to be critically important if its going to have an effect. The key question has to be whether OL-HDF is cost-effective (both economically and environmentally). If the cost-effectiveness analysis stacks up then clearly Ol-HDF should be standard therapy - as yet a quality of life analysis of CONTRAST has failed to show a positive impact of OL-HDF.
2013 will see the publication of numerous guidelines aiming to improve the outcomes of patients with kidney disease. Whilst there will be heated debate about the merits of the CKD classification system or the setting of lipid targets in CKD, it's striking that major international nephrology organisations such as KDIGO and the ISN generally ignore the major elephant in the room when it comes to global nephrology care - namely the right of all citizens around the world to have high quality care irrespective of their ability to pay for such healthcare.
The argument that nephrology care is expensive and many countries cannot afford such care simply doesn't stand up to scrutiny. For example in oil-rich Nigeria or in booming India, end stage renal disease is simply a death sentence for patients who can't afford care. Despite being the 10th largest economy in the world, data from the WHO shows that the government of India only spends 1.1% of its GDP on healthcare. Tazeen Jafar wrote movingly in the New England Journal of Medicine about the death of a Pakistani tailor in 2006 as a result of developing ESRD secondary to type 2 diabetes - bankrupting his family in process. Yet there is nothing 'inevitable' about such deaths - it is too easy to dismiss these deaths as a consequence of poverty rather than a direct consequence of political choices and priorities made by governments. Again data from the WHO shows that the government of Pakistan chooses to spend only a derisory 0.8% of its GDP on healthcare whilst military spending attracts four times as much funding. In contras there are developing countries that choose to make healthcare a priority. For example, Mauritius has been highlighted by the Nobel prize-winning economist Joseph Stigilitz as a role model for many developing countries - it's government spends 6% of GDP on healthcare and has provided free dialysis for all its citizens since 1997.
The problem of health iniquity is not of course just limited to the developing world and is not just about the amount of money spent on healthcare but how it is spent. 16% of Americans have no health insurance resulting in an estimated 45,000 extra deaths a year and this is despite the US spending an astonishing 17.9% of its GDP on healthcare. Of course it is the poor who suffer with Hispanics and African-Americans being particularly affected. As I pointed out in an earlier blog, lack of funding for long term immunosuppression post-kidney transplantation in Medicare insured patients may partially explain the worse outcomes in those insured by Medicare. Similarly a recent small cohort study of African-American live kidney donors published in AJT showed that at nearly 7 years 15.5% had developed an eGFR<60mls/min/1.73m2 and 5.8% had microalbuminuria. Depressingly 52.4% of those donors that had developed hypertension remained untreated. Whilst these differences in outcomes amongst different racial groups effect in part genetic risk factors for disease, it is likely that access to care may also impact on outcomes. Similarly prior to he 'fistula-first' campaign, American dialysis patients were more likely to be subjected to an arteriovenous graft even though the outcomes were known to be worse with a graft, simply because reimbursement favoured the use of grafts.
I am fortunate to work in the UK where the NHS provides free healthcare for all, irrespective of their ability to pay. The NHS was founded in 1948 and was recently memorably celebrated by Danny Boyle in the opening ceremony of the London 2012 Olympics. Like the BBC and the Open University, the NHS is a brilliant, quintessentially British public institution. Of course it is not perfect and there have been issues with quality of care. Yet its strength is that it is valued, cherished and used by a broad swathe of society irrespective of socioeconomic class. It continues to develop with a relatively sophisticated primary healthcare system that is well placed to deal with the epidemic of non-communicable diseases and is widely recognised as being one of the most efficient, cost-effective healthcare systems in the world. It is worth noting that the inception of the NHS was bitterly opposed by medical organisations such as the BMA which worried about the impact of a publicly funded health system on the salary of doctors, prompting the then Health Secretary Nye Bevan to admit that to get the agreement of doctors he had to " stuff their mouths with gold!"
So while national societies and international organisations such as KDIGO and the ISN do great work to promote nephrology care worldwide it is important that we don't lose sight of the bigger picture - early detection of kidney disease and clinical guidelines count for nothing unless governments fund healthcare appropriately. At the moment governments in both the developing and developed world are getting this wrong and are simply not giving adequate priority to publicly funded healthcare and national and international nephrology societies need to start pushing hard on this issue. Universal access to high quality healthcare is a human right not a privilege - now that really is a message worth promoting on World Kidney Day