User blog: Arif Khwaja

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by Arif Khwaja - Tuesday, 19 November 2013, 5:03 PM
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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.

In last weeks NEJM there was some very elegant and preliminary translational work by  Yu and colleagues from Harvard looking at the role of costimulation blockade in FSGS. B7-1 is normally expressed on antigen presenting cells and provides a costimulatory signal necessary for T cell activation by interacting with 2 ligands on the T Cell - CD28 and Cytotoxic T Lymphocyte Antigen 4 (CTLA4). There are a number of costimulation blockers such as abatacept (licensed for rheumatoid arthritis) and belatacept (licensed in psoriasis and renal transplantation).
 
The group observed that B7-1 (CD80) is not expressed in normal kidney podocytes but was expressed in podocytes in biopsy specimens in a number of proteinuric kidney diseases (13 out of 21 biopsies from patients with proteinuric kidney disease were B7-1 positive). Furthermore the observation that B7-1 staining was seen in biopsies from patients with recurrent FSGS suggested that B7-1 expression had been induced during the disease process. The group go on to demonstrate in in vitro podocyte migration studies that overexpression of B7-1 leads to increased podocyte migration. Furthermore this migration is inhibited by abatacept suggesting that costimulation plays an important role in podocyte migration (which is taken as an in vitro 'surrogate' of podocyte effacement and proteinuria). B7-1 overexpression in podocytes caused a loss of beta1-integrin activation which again was reversed by abatacept. i.e. B7-1 promotes podocyte migration  (and therefore proteinuria) through inactivation of beta1-integrin signalling and this is blocked by abatacept. The putative mechanism of action of abatacept is that it binds to B7-1 thereby preventing B7-1 binding to and inactivating beta1-integrin.
 
The group then go on to present data on 5 patients with FSGS who had positive staining for B7-1 on renal biopsy and were refractory to treatment with immunosuppression including steroids and rituximab and plasmapharesis. 4 cases were post transplant and 1 was FSGS in a native kidney. In all cases there was an impressive reduction in proteinuria. In the methodology session the authors state that the treatment was in line with the 'institutional policies' of  Massachusetts General Hospital although its clear what this actually means in practice. The mechanism by which B7-1 becomes expressed in the podocyte is not clear.
 
So does this mean we should be using abatacept for patients with "B7-1 positive" FSGS? One certainly cant justify this on the basis of the a small case series and its important to note that significant numbers of proteinuric patients were B7-1 negative. However this is a promising avenue of future research and is perhaps an example of  'personalised' therapeutics that maybe increasingly seen in the future as the molecular mechanisms underlying glomerular diseases are more clearly delineated. Clearly an important next step is to see whether B7-1 positivity is seen in larger cohorts from different centres and define the mechanisms by which B7-1 expression can be induced.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Arif Khwaja - Sunday, 14 July 2013, 9:20 PM
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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.

Data is presented from Nigeria reporting a median survival of 2 weeks in 760 patients presenting with ESRD with only 6·8% able to continue for more than 12 weeks - invariably bankrupting their families in the process. PD and transplantation are not widely available and again the cost of the fluids seem to preclude the widespread use of PD whilst the infrastructure required to build a transplant program is not there in most countries. 
The authors highlight a number of key issues:
 
i) the scale of the problem of CKD and ESRD is simply unknown in most Subsaharan countries making service planning almost impossible
 
ii) the need to identify and treat kidney disease early in those at high risk of kidney disease - in part this will involve a strategy dealing with non-communicable diseases such as diabetes and hypertension. These can be delivered cheaply by trained healthworkers rather than more expensive doctors as was shown in Iran.
 
iii) finally the authors call for a strategy to treat those who develop ESRD - the need to develop an infrastructure for transplantation and the need for dialysis. This of courses raises important questions of equity - is it worth funding RRT in such resource-poor environments when the cost in countries such as  Malawi, is almost 1000 times the national per-head health expenditure and 65 times the gross national income per head.
 
There are a few other points that aren't discussed that are perhaps also worth considering:
 
i) even within Sub-saharan Africa that are significant variations in care that can't be explained by money. For example the GNP per capita for Nigeria and Sudan are broadly similar and less than $2000. Yet Sudan has been able to provide RRT for its population - this must reflect political decision making and prioritisation.. I was fortunate to hear Professor Abu Aisha ( nephrologist and ex minister of health in Sudan) give an inspirational talk a few months ago about how nephrology (and healthcare in general) were transformed in a low-resource setting when the political will is there.
 
ii) clearly prevention is the key -managing non-communicable disease, improving obstetric care and infectious disease management, preventing and treating HIV will all impact on the numbers with ESRD. i.e. its essential that resources arent nephro-centric but rather focussed on key public health areas which in turn feed the ESRD epidemic. And of course spending money on eduction, sanitation  and clean water supply will all positively impact in public health in general as well as ESRD and CKD numbers
 
iii) whichever way you look at the problem you cant divorce it from politics and economics. The Nobel Prize winning economist Joseph Stigilitz has highlighted Mauritius as an example of country whose healthcare system has been transformed as a result of political decisions. Public health policy is de facto political and clinicians shouldn't shy away from getting involved in controversial political debates.
 
iv) there has to be an onus on industry and academia to come up with cheap, technological solutions for RRT. Cheap fluid for PD, aggressive transplantation, a cost effective model for dialysis are all areas of urgent research.
 
v) Like myself both the first and senior author of this paper are not primarily based in Africa  ( the middle author is Prof Naicker, a nephrologist from South Africa) but in a high-income western economy. This in itself is a problem. Journals such as the Lancet should perhaps try to provide a platform for African clinicians to come up with local solutions  and models of care. I hope some of the OLA readers working in Sub-Saharan Africa will educate me on what needs to be done......
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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There is an interesting paper published in this weeks NEJM by Suthanthiran and colleagues evaluating the predictive value of urinary biomarkers in acute cellular rejection. They collected 4300 urine samples from 485 kidney grafts from day 3 post-transplantation to 12 months. They measured absolute levels of  urinary mRNA of CD3e, perforin, granzymeB, proteinase inhibitor 9, CD103, Inteferon-inducible protein -10 (IP-10), CXCR3 and TGF-beta1 and 18S ribosomal RNA (rRNA). They came up with a three gene signature of CD3e, IP-10 and 18S rRNA to discriminate acute cellular rejection from those not displaying rejection.
They demonstrated an area under the curve (AUC) of 0.85, p<0.001 by ROC curve analysis for this three gene signature discriminating aucte cellular rejection from non-acute cellular rejection. In the external data validation set the AUC was lower at 0.74 though this apparently wasnt significantly different from the AUC in the primary data set. Interestingly in sequential urine samples there was a significant incraese in the 3 gene signature in the 30 days prior to the development of acute rejection, raising the possibility that this signature could be used to identify incipient patients who are about to develop rejection. There is a long history of groups looking for non-invasive markers of rejection (either for mRNA or a proteomic approach) and this is certainly an interesting addition to that literature.
The statistical methodology in this paper is complex and is beyond my area of expertise but my immediate thoughts are:
 
i) is an AUC of 0.74 to  0.85 really good enough for a diagnostic test? Probably not!
ii) In an era of daycase US-guided renal biopsies are we overplaying the risk of transplant biopsies? The risks of biopsies are small (but not zero) and its not clear to me that there is a clinical need to replace a gold-standard test with a non-invasive test. A biopsy will of course provide other invaluable therapeutic information such as evidency of viral infections and drug toxicity which maybe difficult for a non-invasive test to do.
iii) the increase in the trajectory of the gene signature prior to the diagnosis of rejection is interesting as it raises the tantalising possiblity that such an approach may help diagnose rejection earlier. However no comparative data is presented to show what happened to either GFR or creatinine in the 30 days prior to the diagnosis of rejection. i.e. the paper didnt really answer the question whether this test was any better than measuring the serum creatinine
iv) clearly prospective studies in other data sets comparing to conventional measures of graft dysfunction will be helpful- till then I think this kind of approach to diagnosing rejection has a long way to go
 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Arif Khwaja - Friday, 7 June 2013, 6:11 PM
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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.

 

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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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) >3ml/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.

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

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Arif Khwaja - Sunday, 17 February 2013, 10:41 AM
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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.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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The KDIGO 2012 CKD guidelines which were recently published are available for all to read. Here are my immediate thoughts:
 
i) There are 2 chapters on defining and identifying CKD and progression and only one chapter on the management of progression of CKD and its complications. This tells you all you need to know about the obssession with epidemiological data in the nephrology literature at the moment. This is true of not only CKD but AKI as well
 
ii) Worth reminding ourselves that there is not one single licensed therapy for preventing the progression of CKD - its disappointing that of all the research recommendations made not one focussed on the need for licensed therapies in progressive CKD and how to collaborate with industry/academia to deliver this
 
iii) The classification system is absurdly complex and is a great example of  the dangers of taking an epidemiologically useful tool for research and putting it into the clinical arena. I gave a talk to some family doctors last week and went over the KDIGO classification system... all of them found it confusing, complex and nobody could understand why there needed to be another revision of the staging system. One of the doctors just looked at the classification and said " that just gives me a headache".....
 
iv) has anybody met a busy practicing nephrologist who thinks that microalbuminuria should be considered as a sole definer of CKD?
 
v) Can anyone explain how differentiating between CKD 1 and 2 based on current eGFR equations a) makes sense and b) will change patient management and improve outcomes
vi) as discussed the age neutrality of the classification simply does not stand up to any scrutiny... we all know that an eGFR of 40mls/min means different things in a 20 year old and a 70 year old as was powerfully shown by O'Hare and colleagues several years ago
 
vii) I have yet to see a convincing rebuttal to the critique of the CKD classification system put forward by the likes of Glassock and Winnearls and others several years ago
 
vii) KDIGO either needs to remove the term 'Global' from its title or start addressing the healthcare needs of the global population. The earlier guidelines on transplantation did discuss models of care in low income countries yet here there is no such discussion here. Its great to talk about patient activation, psychosocial support and the need for conservative care for those of us who work in affluent societies. Yet we know large swathes of the global population have no access to any kind of nephrology care. To provide absolutely no discussion or direction for how low/middle income societies should deal with CKD at best displays a lack of imagination and at worst just highlights the academic and geographical myopia of those who wrote guidelines.
 
 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Arif Khwaja - Wednesday, 16 January 2013, 9:52 AM
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The UK Membranous Nephropathy Trial which I had blogged on in an earlier post here has now been published in The Lancet. Most of the data was presented at The ASN and is covered in my earlier blog but its worth reiterating a few points. 108 patients who had at least a 20% decline in excretory renal function over 2 years  were randomised to chlorambucil+ steroids, ciclosporin monotherapy or supportive care. No data was provided about ARBs but 82% of the cytotoxic group, 92% of the CyA group and 100% of the supportive care group were on ACEi. The primary endpoint was a  further 20%  decline in excretory renal function. 58 % of the cytotoxic group experienced this compared to 81-84% of the other 2 groups. The outcomes with CNI and supportive care were comparable. 36 months after randomisation the greatest mean reduction in proteinuria was in the cytotoxic group of 2.2g/24 hours. Serious adverse events were much more common in the cytotoxic group (61%) vs 49% in the CyA group and 42% in the supportive care group. Most of these adverse events were related to haematological complications from myelosuppression with chlorambucil and metabolic disturbances with steroids. Its worth noting that at randomisation the kidney function was reasonable in all three groups with a creatinine clearance of around 50mls/min.
 
My thoughts are as follows:
 
i) this is an excellent RCT that establishes that cytotoxic therapy should be the preferred therapy for those with progressive membranous nephropathy. This adds to a body of earlier work from Jha and Ponticelli that suggests that cytotoxic therapy is the treatment of choice for those with progressive disease who dont undergo spontaneous remission. There is no role for CNIs in such patients.
ii) as acknowledged in the excellent discussion the adverse events with such therapy is a problem but its also worth noting that adverse events are also pretty common in the supportive care group suggesting the disease itself can be fairly disabling
iii) there was no data presented on progression to ESRD although given the trajectory of the data presented I think its safe to assume that cytotoxic therapy would reduce the risk of progression to ESRD. Given the time it took to conduct this study I dont think one can reasonably expect there to be a study of membranous that has ESRD as its endpoint!
iv) the authors themselves state that Ponticelli has showed (subsequent to the start of the study) that cyclophosphamide and chlorambucil are equally effective.
v) Clearly as phospholipase a2 receptor antibody testing starts to be introduced into clinical practice future trials in membranous maybe able to better identify those who would benefit from immunosuppressive therapy.
vi) Finally given the positive observational data of Rituximab from the Remuzzi group and from the Mayo Clinic the next obvious trial to do in membranous would be to compare rituximab to cytotoxic therapy not only in terms of remission and progression but also evaluating safety and cost-effectiveness. Until such data is available it is difficult to justify using Rituximab as first line therapy as there have been no studies comparing it with simple supportive care or with active cytotoxic therapy.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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by Arif Khwaja - Wednesday, 26 December 2012, 11:18 PM
Anyone in the world

 

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

 

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