De Vriese and colleagues in Belgium argue in teh january issue of KI that all patients on RRT should be screened for coronary artery disease (CAD). This implies that symptomatic but also asymptomatic patients should be screened.
Their argument is based on the fact that a very high prevalence of CAD in chronic dialysis patients including up to 53% in asymptomatic patients and 83% in those with diabetes. Also higher prevalence in older dialysis patients. Consequently, the majority of dialysis patients with angiographically documented CAD are asymptomatic (Ohtake et al).
They show data confirming the good predictive value of a positive Myocardial Perfusion Scintigraphy (MPS) for CAD. Adenosine, dipyridamole or dobutamine stresss MPS have all been shown to have high predictive values for CAD; the presence of reversible ischemia upon stress MPS closely correlating with the gold standard of coronary angiography (Rabbat et al, 2003).
The question that comes to mnd is why screen asymptomatic patients as data in non CKD patients shows that survival in such patients is not affected by intervention and therefore investigations not recommended. Furthermore, there is a good body of evidence that medical therapy? The authors argue that dialysis patients are at much higher risk of CAD and related mortality thus justifying screening and intervention. The published data, albeit limited, suggest that in dialysis patients with CAPD treated with PCI or CABG have a survival advantage compared to those on medication only.
The authors advocate screening all those on dialysis listed for transplantation arguing the high prevalence of asymptomatic patients justify such an approach rather than current guidelines recommending screening only in those with a histroy of revascularisation, a signficant reduction in LV function, or symptoms suggestive of CAD/CHF. Guidelines also recommend screening selected high risk patients which woukld automatically, in my view, include diabetic patients.
The authors advocate a large RCT that examines the incremental benefit of revascularisation in addition to medical therapy in asymptomatic dialysis patients.
I remain unconvinced on a cost/benefit analysis basis that all dialysis patients should be screened as their editorial review suggests a risk of asymptomatic CAD predmoninatly driven by diabetic patients on HD. It would therefore be more cost-effective to screen as currently recommended by international guidelines those at high risk: diabetics, history of CAD, those with an abnormal echocardiogram, etc...
It would be desirable to have a cheap and non invasive test/biomarkers that predicts the presence of subclinical CAD. Cartiac Troponins may prove to be such a test. Recent high sensitivity assays showed a considerable higher circulating levels in asymptoamtic CAD ESRD patients (Jacobs et al).
De Vriese et al. Should we screen for CAD in asymptomatic chronic dialysis patients. Kidney Int. 2012;81:143-151.
Ohtake et al. High prevalence of occult CAD in patients with CKD at th einitiation of renal replacement therapy. JASN 2005;16:1141-1148.
Rabbat et al. Prognostic value of myocardial perfusion studies in ESRD patients: a meta-analysis. JASN 2003; 14:431-439.
Jacobs et al. Hemodilayusis patients longitudinally assessed by highly sensitive cardiac troponin T and commercial cardiac Troponin T and I assays. Ann Clin Biochem 2009;46:283-290.
The results of the LUNAR study have finally been published in Arthritis and Rheumatism nearly 3 years after being first presented. The study was an RCT of 144 patients looking at the impact of Rituximab (4 doses of 1gm) as add on therapy to steroids and MMF in patients with Class III and IV lupus nephritis. Patients received two doses of methylprednisolone and the steroid taper was from 60mg to around 10 mg at 4 months. The primary endpoint was a composite of CR+PR. At 12 months there was NO significantdifference in renal complete remission (CR) or partial remission (PR). Those in CR/PR were 56.9% in the Rituximab group and 45.8% in the placebo group. CR and PR were rigorously defined by creatinine, proteinuria and haematiuria. Interestingly there was a significant reduction in the C3, C4 and DsDNA (all secondary endpoints) in the Rituximab group and at 72 weeks proteinuria was lower in the Rituximab group. Also in a pre-specified sub-group analysis of race, the primary endpoint was achieved in 70% of black patients receiving Rituximab versus 45% of black patients who received MMF an dsteroids only – this difference wasn’t statistically significant.
This really well designed study seems to suggest there is no role for Rituximab in lupus nephritis in contrast to earlier observational data. Does this mean we should never use Rituximab in lupus nephritis? Well my thoughts are as follows:
- Clearly for most patients with lupus nephritis treated with MMF and steroids, Rituximab will have no added benefit
- We don’t know if there is a role of Rituximab in patients with difficult disease refractory to cyclophosphamide/MMF – as these kinds of patients weren’t in the study. Like most recent studies in LN kidney function was well preserved.
- The study wasn’t really designed to address the role of Rituximab as a steroid minimising/sparing agent as advocated by Imperial College and others. To do this would require a much more aggressive steroid taper than that in the study.
- Finally but importantly as always the choice of endpoint is important in determining whether a study is positive or negative as we have seen in the lipid lowering studies. The study was powered to detect a 25% improvement in renal response rate but this power calculation was heavily skewed towards detecting complete remission rather than partial remission. Thus the authors state that with this sample size the power was less than 70% to detect a 25% improvement in renal response rate where the remissions were predominantly partial rather than complete. Thus whilst the partial remission rate was 31% in the Rituximab group compared to 15% in the placebo group the study was underpowered to detect this difference. Therefore Rituximab maybe having a clinically meaningful effect that this study wasn’t powered to detect.
- Class V LN was excluded and its worth noting that for idiopathic data there is increasing evidence of efficacy of Rituximab
Based on this paper my own practice will continue to be to use MMF and Prednisolone as first line therapy with Cyclophosphamide reserved for those with severe disease. I tend to use Rituximab in i) those who have not responded to MMF/cyclophosphamide ii) those who are unable to take cyclophosphamide ( due to previous exposure or fertility issues) and iii) those who are unable to come off steroids and/or have problems with steroid toxicity.
2. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids.Pepper R, Griffith M, Kirwan C, Levy J, Taube D, Pusey C, Lightstone L, Cairns T. Nephrol Dial Transplant. 2009 Dec;24(12):3717-23. Epub 2009 Jul 17.
- Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab (LUNAR) study. Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G; for the LUNAR Investigator Group. Arthritis Rheum. 2012 Jan 9. doi: 10.1002/art.34359.
Anyone who has been to a GKA masterclass will know that a key learning message from Professor El Nahas' session on 'how to read a paper' is to assess whether the findings are relevant to your healthcare setting. I was thinking about this recently when a large RCT was recently published in NEJM evaluating whether low molecular weight heparin reduces mortality in acutely ill medical patients- this was of interest as in the UK we are aggressively audited to make sure all acute admissions get prophylactic heparin. The outcome of this trial of more than 8000 patients was negative but what interested me was where the trial was conducted - China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. One question that arises is how applicable this data would be to say a Uk setting? We know that in the UK there are huge variations in outcome for the same diseases in different hospitals- despite that fact that we have only one major supplier of healthcare - the NHS. So I imagine both care and patient characteristics maybe very different ( not better or worse just different) in the UK than say Tunisia. Similarly in two trials of belimumab in SLE the BLISS 52 trial reported relatively positive outcomes whilst BLISS 76 seemed to suggest that belimumab had a more marginal effect. Some have suggested that this was because BLISS 76 was conducted predominantly in the USA and Europe whilst Bliss 52 was conducted predominantly in Asia and Eastern Europe - the implication being that either the disease itself or standard care is different between say the USA and Asia My own thoughts are that all we can do is look at data and critically evaluate the relevance to the healthcare setting we practice in. Of course it also suggests that we all have a responsibility to try if possible to get involved in clinical research conducted in line with good clinical practice to ensure evidence-based decision making continues to develop.
See : http://www.nejm.org/doi/full/10.1056/NEJMoa1111288?query=TOC
With the epidemic of type 2 diabetes, obesity and an ageing population much of modern day nephrology focusses primarily on cardiovascular risk management - i.e. blood pressure, lipid and glycaemic control. One question I've always asked myself is whether the traditional model of a patient visiting a doctor in a clinic at two to three monthly intervals is clinically useful or cost effective. Many of the lifestyle interventions such as diet, exercise, stopping smoking, salt restriction etc dont actually require specialist clinical input whilst for many patients algorithms for BP, lipid or glycaemic control are relatively simple and well established through national guidelines. Indeed in the UK, some specialist nurses appropriately trained in prescribing having taken on an important role managing diabetes and hypertension in primary care. Furthermore it is clear that in middle and low income countries ( where there is a real epidemic of non-communicable diseases (NCDs)) such a doctor-centric model of care is simply not financially viable.
In this weeks Lancet there is an interesting analysis of the Iranian approach to NCDs with an analysis of their approach to rural primary health care. Their model known as the Behvarz system uses trained community health care workers to serve rural populations. These workers are trained for 2 years and receive a salary that is 1/6th that of a doctors salary. Between 1996 and 2002 as part of a national action plan for the prevention and control of diabetes, Behvarz workers were trained to identify those at high risk of diabetes, provide lifestyle advise and follow up those diagnosed with diabetes to monitor for complications and promote adherence and identify patients who are running into problems to doctors . Data from the NCD surveillance survey in 2005 ( a large health examination survey of nearly 90,000 individuals aged between 15-64) was combined with socio-economic data and data on the density of Behvarz workers to study the impact of the scheme. Treatment reduced plasma glucose by 1.34 mmol/l in rural (i.e. Behvarz areas) compared to 0.21 mmol/l in urban areas. With respect to blood pressure the results were slightly better in urban areas though its important to appreciate that blood pressure management had not been incorporated into the Behvarz system.
Whilst the study is not a RCT of two different models of care this large, high quality dataset makes interesting reading. The better control of diabetes in rural areas did seem to be related to the use of Behvarz workers who perhaps played a key role in ensuring adherence to therapeutic plans. If healthcare systems around the world are to rise to the challenge of NCDs then we will need to develop alternative, cost-effective models of care - and we will need to challenge whether what doctors do can be delivered (or complemented) by other healthcare workers in a more cost-effective way.
see Farzadfar and colleagues http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61349-4/abstract
A recent publications by Tonelli and his colleagues in Edmonton, Canada in KI December 2011, highlights the risks associated with a high estimated GFR (eGFR). Using data from a population data base of 1,526,437 patients, they conclude that a high eGFR is associated with an increased risk of all cause mortality. They estimated that those with an eGFR of 60-74.9ml/min had the lowest risk compared to higher hazard ratio of 3.7 and 1.8 in those with eGFR>105 and 90-104.9ml/min respectively. Such risk is enhanced in those with dipstick positive proteinuria.
In their discussion they offer a number of possible explanations.
I have reservations about a number of points related to that publication:
1. It relied on a ESTIMATED GFR based on the MDRD equation known to be inaccurate at a measured GFR >60ml/min; in fact many biochemistry laboratories estimate the inaccuracies and imprecision of MDRD formula at eGFR>90 so significant that they do not give a quantitative value above that level of calculation >90ml/min. So to differentiate with a single Cr estimation and an inaccurate formula measured GFRs of 74.9 to 104.9 to >105 is effectively a misleading waste of time...!? The authors somewhat validated their findings with the CKD EPI equation although I an uncertain about that equation adequacy in those with mGFRs between 75-105ml/min?
2. ESTIMATED GFR is not MEASURED GFR; whils this seeems obvious they have become increasingly interchangeable in recent nephrology literature..? Even clinical trials interchange eGFR with mGFR....like the recently published BEAM stduy where the lowering of sCR by the trial agent was automatically assumed to reflect an improvement in kidney function rather than tubular damage and increased urinary leakage of creatinine...?
As we all know, eGFR is a reflection of serum creatinine levels that can be affected by a number of factors including wasting, sarcopenia and overal body muscle mass. The eGFR formula corrects and adjusts for body surface area but not body muscle mass. Patients with low eGFR may have lower serum creatinine and lower muscle mass due to a number of factors independently of their true GFR.
In fact, it is well known that low serum and urinary creatinine measurements as well as low muscle mass are associated with increased mortality risk. Whilst the authors acknowledge that wasting associated with underlying illness/comorbidity may explain their findings, this is not the thrust of their discussion.
A better title for this publication would have been: "Low serum creatinine may be associated with increased risk of adverse outcomes..."
It is high time that we go back to basics and remember the ESTIMATED GFR is what it is...an estimate based on serum creatinine levels and NOT a automatic reflection of TRUE GFR; above a GFR of 60-75ml/min it is not even an ESTIMATE but more likely to be a GUESTIMATE....!!!!
Let's not put too much emphasis on guestimates and pay more attention to underlying co-morbidities that explain wasting, low serum creatinine and high risk of mortality in some members of our communities.
On Tuesday of this week, the ALTITUDE study investigating the effect of Aliskerin (a renin antagonist) on Diabetic Nephropathy has been stopped for lack of efficacy.
Is that another nail in the coffin of RAAS inhibition in CKD and Diabetic Nephropathy or is it a misunderstanding of the nature of modern day diabetic kidney disease?
Increasingly the patients with diabetes and CKD we see at the Sheffield Kidney Institute are older T2DM patients with longstanding hypertension, often predating the diagnosis of DM, atherosclerosis and minimal (<1g/24h) proteinuria; those are likely to have renal atherosclerosis and ischemic nephropathy. These are unlikely to respond to RAAS inhibition and may in fact be harmed by these agents and their combination (see data from ONTARGET).
The RAAS inhibition story in DN started in 1984 in experimental animals (Zatz et al/Brenner et al.) of T1DM. They were apparently confirmed in the Lewis study published in NEJM in 1993 , but when you read carefully this publication you realised the patients selection bias; those with heavy proteinuria at baseline were in the placebo group, those with milder proteinuria in the captopril group...so selection bias from onset not to mention the fact that BP systolic and diastolic was lower in the captopril group! Consequently, if beneficial at all these agents would be best used in young, T1DM with heavy proteinuria reflecting severe microvascular disease...not older T2DM with ATS and renal ischemia...
So perhaps, it is high time for nephrologists worldwide to:
1. Distinguish diabetic nephropathy (T1DM) and diabetic nephropathy (T2DM)
2. Get off the RAAS inhibition bandwagon as this approach can do more harm than good if patients selection is not carefully considered.
In fact, we published preliminary data suggesting that STOPPING these agents in T2DM may lead to IMPROVEMENT in the kidney function of some patients with T2DM and advanced CKD (Ahmed et al, 2011)!
A number of publications have recently linked AKI to the development or progression of CKD.
In the November issue of cJASN:
Thakar et al as well as an editorial on the topic highlight this important issue.
Thakar and colleagues report the increased incidence of CKD in elderly diabetics who develop one or more episodes of AKI.
This publication along with another 5 reviewed in the editorial by Bydash and Ishani stress teh association between AKI and CKD.
In the Thankar et al paper, elderly diabetics with CKD3 and significant proteinuria were at the highest risk.
I ask myself, what do T2DM, with CKD and heavy proteinuria have in common?
The answer is the "Elephant in the Room" that everybody chooses to ignore... INHIBITION OF THE RAAS!!!
So I suspect that these older diabetics with CKD3 ar eall on the dreaded ACE inhibitors, ARBs or a combination of both when in reality they have significant underlying atherosclerosis, CAD as well as peripheral vascular disease; also most likely to be suffering from atherosclerotic renovascular disease and ischemic nephropathy.
I therefore urge the authors of these publications to examine the medication these patients are on and the relationship between RAAS inhibitors and the development of AKI/CKD.
Also, I urge Nephrologists to spare their older patients with T2DM and atherosclerotic manifestations (that most have) the use of inhibitors of the renin angiotensin aldosterone system (RAAS). These are often immediately detrimental to these patients kidney function. They may also accelerate the decline of kidney function as shown many years ago by Suissa and colleagues in Canada and by Onuigbo and colleagues in the US.
BUT also, they may constitute an added risk to elderly patients who have an AKI insult thus further compromising their acute insult and further compromising their pre-existent CKD.
So after analysing the effect of obesity and phosphorus yet another post-hoc analysis from the REIN study is about to be published in JASN ! This analysis looked at the effect of dietary salt intake (as measured by 24 hour urinary sodium and creatinine) suggests that those with high salt intake were more likely to progress to ESRD and that this was mediated by attenuating the anti-proteinuric effects of ACE-I. Among those with low, medium, and high sodium intakes, the incidence of ESRD was 6.1 %, 7.9 and 18.2 per 100 patient-years, respectively (P<0.001). Somewhat counter-intuitively there was no difference in blood pressure and the association between salt intake and progression was lost when taking into account changes in proteinuria during follow up - leading the authors to conclude that the anti-proteinuric effects of ACE-i were mitigated by salt intake.The authors suggest that expansion of the sodium pool leads to glomerular hyperfiltration and activation of the renal RAS ithereby mitigating the anti-proteinuric effects of ACEi.
It has been established for many years that diuretics and salt restriction both augment the anti-hypertensive effects of ACE-i and so it is surprising to see no difference in BP between the hogh and low sodium groups. As said before I am never comfortable with the use of post-hoc analysis to try to elucudate the mechanism of action of a drug or a treatment recommendation. However the article reinforces the need salt restriction in the CKD population and the importance of factoring salt intake into any trials of progression. Whilst salt restriction is clearly important I'm not sure I share the authors belief that salt restriction can be achieved easily by 'small inconveniences of minimal dietary restrictions" - my personal experiene is that all dietary interventions are difficult to achieve and require considerable dietic resource.