NATIONAL COURSE FOR RENAL FELLOWS: ORIGINS OF RENAL PHYSIOLOGY

Places are still open for the 10th running of this one week course, held annually at the Mount Desert Island Biological Laboratories near Acadia National Park, in Maine.  

The course provides a one week research experience which will:

Broaden your understanding of renal physiology

Make you a better renal investigator

Make you a far stronger bedside teacher

Make you a better teacher of renal physiology

Enhance your clinical understanding of renal diseases

The fellows who have taken the course over the past decade have loved it, and many have found it to be transformative.

When does the course run?   8/31/14 – 9/7/14.  

What does it cost?  The course is funded by the NIH, so instruction, room and board are at no cost.  The only cost is for travel to and from Maine (or Boston, because we can help trainees reach Maine from Boston).

How do I find out more and apply?    The website for the course is: http://www.mdibl.org/courses/Origins_of_Renal_Physiology_Renal_Fellows/114/

Mark L. Zeidel, M.D.

Course Director

NephMadness 2014 Part 8 - Biologics Bracket

This is a really exciting bracket and is full of new agents that will hopefully lead to major advances in our field. Acthar is the outlier here as, even though it is a peptide, it is not an antibody. For all the other agents I find it helpful to visualize what the antibody is targeting and on which cell type. Hopefully these cartoons will help. I think Rituximab and bortezomib should always go hand in hand when treating and auto- or alloimmune process as rituximab eliminates immature and naïve B cells and bortezomib eliminates B cells that have matured into antibody producing Plasma cells. There are some small trials reporting the use of both agents including a phase 2 trial in Waldenstroms Macroglobulinaemia but a large clinical trials using both these agents would be great.

In 2005 the FDA approved abatacept for RA after clinical trials showed benefit. However, there was evidence that this biologic might not be so efficacious in transplantation. Co-stimulation blockade on individual CD4+ T helper-cell subsets suggested a resistance of IL-17 secreting CCR6+ memory type 17 T helper cells (TH17) cells to CD28 and CTLA-4 blockade by abatacept. Effectively, abatacept inhibits the responsiveness of the total population, but a subset of cells are resistant to this inhibition. Belatacept is a second-generation CTLA-4 Ig fusion protein that differs from abatacept by only 2 amino acid substitutions (L104E and A29Y), which gives rise to slower dissociation rates from both CD86 and CD80. Subsequent research revealed this agent to be 10-fold more potent in vitro, and a more effective inhibitor of renal transplant rejection than abatacept. The subsequent BENEFIT trials proved belatacepts efficacy in transplantation.

CR1 or complement receptor type 1 or C3b/C4b receptor or CD35 is protein encoded the CR1 gene. This gene is in the RCA (regulators of complement activation) cluster region of human chromosome 1. This region includes the CFHR 1-5 and CFH genes. All these genes when mutated can cause immune-complex glomerular diseases such as MPGN. This CR1 protein also accounts for all the Knops blood group antigens. Reductions in CR1 or down regulating mutations can also cause SLE. Soluble CR1 may be useful in transplantation also. One study showed that sCR1 treatment improved 24 hour creatinine and inflammatory profiles post transplant in rats transplanted after brain death.

As precursors to the plasma cells that secrete antibodies, B cells are central in the pathology of SLE. Increased B-cell activation is due in part to increased levels of growth factors, including B-lymphocyte stimulator (BLyS), also called B-cell activating factor (BAFF). Belimumab is a human IgG1 monoclonal antibody that binds to soluble BLyS and thus prevents it from binding the BAFF receptors on B cells. So you can see where the trial names BLISS-52 and BLISS-76 come from, the numbers refer to the number of weeks the trials lasted. BLyS is a growth factor required for B-cell survival, maturation, and activation; germinal-center formation; the development of B cells into plasma cells; and immunoglobulin production. Many maturing B cells are completely dependent on the binding of BAFF receptors by BLyS to survive and mature. Memory B cells cells lack BAFF receptors. At least 50% of people with SLE have elevated plasma levels of soluble BLyS and there is a weak but significant correlation between high levels and active disease. Unfortunately patients with severe active LN were excluded from the BLISS trials.

For me Rituximab was the favourit in this groups as it is probably used in the greatest variety of diseases.

Thanks for reading and i hope you all learned something as i learned alot from NephMadness 2014. Now go to the NephMadness site and submit your brackets if you have not done so already!

NephMadness 2014 Part 7 - Electrolyte Bracket

The electrolyte bracket contains a mixture of the old staples of nephrology mixed with some new kids on the block trying to muscle in on established territory, Vaptans vs hypertonic saline and ZS-9 vs Kayexalate. Hypertonic saline is well established and works when used correctly. In my experience inadequate monitoring and insufficient lab testing always complicates the correction of severe and acute hyponatremia. Severe hyponatremia has potentially devastating consequences and so should be managed in an ICU setting where frequent labs can be drawn and most importantly acted upon. The role of Vaptans is probably more in the chronic setting, in particular for longstanding hyponatremia in the setting of heart failure. In fact the SALT 1+2 trials excluded patients with acute symptomatic hyponatremia. Dr Berl wrote a nice review in KI.

Bicarbonate is center stage in the 2 and 7 seed match up. Bicarbonate for acute acidosis such as lactic acidosis, when extreme, is widely used I would imagine. This is despite lack of good evidence to suggest it improves outcomes. However, when faced with severe acidosis it makes physiological sense to give alkali. Another area were iv bicarbonate has fallen out of favor is in cardiopulmonary resuscitation. The 2010 ACLS guidelines recommended against the routine use of iv bicarbonate. This was due to fears of it causing intracellular acidosis, hypernatremia, respiratory depression and metabolic acidosis once perfusion is restored. One study from the 1990s looked at 273 successful out of hospital cardiac arrest outcomes. 58 patients got no HCO3 and had short CPR times (7.4 +/- 5.5 minutes). 215 patients did receive HCO3 and had significantly longer CPR times (23.3 +/- 13.5 minutes, (P =< 0.001). Initial emergency department blood gas results of both groups were not significantly different. No patients in the no HCO3 group had hypernatremia (sodium [Na]+ greater than 150), whereas four patients (2%) in the HCO3 group were hypernatremic. Eight patients (14%) in the no HCO3 group and 37 patients (17%) in theHCO3 group were alkalotic with pH values greater than 7.49 (P = NS). Six patients (10%) of the no HCO3 group and 24 patients (11%) of the HCO3 group had a metabolic component to the alkalosis as defined by a positive base excess value (P = NS). These are interesting findings given that these patients are the sickest and probably most acidemic you will encounter!

Despite this entire blurb I went for serum anion gap in this bracket!Very useful equation.

NephMadness 2014 Part 6 - Kidney Stone Bracket

In the kidney stone bracket I think the most disappointed team must be XO inhibitors. Allopurinol has been around for a long time and is one of the mainstays of treatment for gout. More recently, febuxostat hit the scene and can also lower uric acid. The most interesting issue relating to uric acid (for me) is the evidence linking elevated uric acid with risk of developing CKD. This idea is backed by experiments in rats. Raising the uric acid level in rats can induce glomerular hypertension and renal disease as noted by the development of arteriolosclerosis, glomerular injury and tubulointerstitial fibrosis. Some pilot studies in human suggest that lowering uric acid levels can slow the progression of renal disease. If these findings are significant large RCTs, the old man Allopurinol and the young pup febuxostat would be catapulted into the stratosphere! A good review of this literature is found here. Despite these interesting findings, CT scan beat XO inhibitors for me. I think CT scanning, for good or for bad, is ubiquitous in medicine and won by shear prevalence! Another very interesting match up and some learning for me was the Dr Pak vs Dr Coe match-up, two heavy weights of renal stone disease. I vaguely remember learning about Randall’s plaques and supersaturation of urine years ago. The loser of this match up must surely be disappointed!

Live Kidney Donation: What’s the risk?

As ESRD prevalence continues to increase, the kidney transplant list continues to grow meaning longer waiting times for deceased donor transplantation. Living donation (LD) provides the best outcomes for patients with ESRD and is considered safe for the donor when they are screened effectively. However, although we have data demonstrating low morbidity and mortality associated with living donor nephrectomy, our longer term data has traditionally been flawed. This is primarily because previous studies examining the long-term risk associated with LD has used the general unscreened population as comparators. Individuals who are accepted as living donors have passed rigorous screening and are therefore a well group, likely more so than matched general population controls. A study from Norway included controls matched for age, race and year of birth and showed overall and cardiovascular mortality was lower for kidney donors. A US study employed NHANES controls who were matched for age, sex, BMI and race and reported equivalent risk of ESRD and patient survival. Therefore, our counselling of potential donors was limited to comparisons to the general population where we could point to no increased renal or patient survival risk but we had little data on actual risk of similarly matched controls who did not donate. In recent months we have 2 new studies which give us more accurate data.

The first study was published in KI and included over 1900 kidney donors from Norway between 1963 and 2007. Crucially, the control group comprised individuals deemed eligible for donation (n>32,000). Eligibility was determined from a population cohort with BP<140/90 mm Hg (on no anti-hypertensives), BMI<30 kg/m² who rated their health as ‘good’ or ‘excellent’. Individuals were excluded if they had diabetes or cardiovascular disease. Note that the authors had no data on renal function or albuminuria for the controls. The results demonstrated that donors had a significantly increased long-term risk for ESRD (hazard ratio 11.38!), cardiovascular mortality (HR 1.40) and all-cause mortality (HR 1.30). Of note, 1519 of the donors were first-degree relatives, all cases of ESRD occurred in living related donors and the etiology was immunological in nature, reflecting a likely genetic component to the renal disease in the donors.

Another study recently reported in JAMA from the US included a cohort of >96,000 kidney donors between 1994 & 2011, >20,000 matched controls from NHANES III and examined ESRD risk alone. Controls were gathered by excluding those with identified contraindications to kidney donation (9364 qualified as eligible). They were matched by age, sex, race, educational background, BMI, BP and smoking history. Over a median follow up of 7.6 years, the donors had an increased risk of ESRD. Specifically, the risk of ESRD was 30.8/10,000 in donors V 3.9/10,000 in the matched non-donor controls (P <0.001). The risk was particularly high in black individuals (risk of 74.7/10,000 in donors V 23.9/10,000 in non-donors). Interestingly, white donors (22.7/10,000) had a similar risk of ESRD to the black non-donors with white non-donors having extremely low risk of ESRD in this cohort (0.0/10,000; p<0.001 V white donors). The lifetime risk of ESRD in donors was still significantly lower than unscreened non-donors (i.e. general population) at 90/10,000 V 326/10,000 (see figure).

These studies reaffirm our belief that lifetime risk of ESRD in LD is no higher than in the general demographically-matched population. However the new data suggest that ESRD risk is unsurprisingly higher than healthy screened controls, deemed eligible for donation but who have not donated. The ESRD risk for donation appears to be particularly increased for African Americans, likely due to genetic factors such as presence of APOL1 risk variants. However, the overall magnitude of the risk is small and I think the findings are reassuring. The mortality data from the Norwegian study is not particularly surprising given the robust association between reduced kidney function and mortality in the general population. These studies still have limitations including data ascertainment differences between donors and controls. Also, the control groups may not be perfect but do represent an improvement over previous studies using the unscreened general population. We are now is a position to counsel our living donors with more accuracy regarding the risks of living donation. In my experience, most living donors are happy to accept a small future risk of adverse outcome to donate to a loved one.

NephMadness 2014 Part 5 - Renal Replacement Bracket

In the Renal Replacement bracket we see all the usual players, except for convective clearance, which is not in mainstream use in chronic dialysis units in the US. It is relatively unknown this side of the Atlantic (west of!) but online hemodiafiltration (olHDF) is used in many parts of Europe. olHDF utilizes diffusive clearance and convective clearance during a regular dialysis session. To use convective clearance or hemofiltration a different machine is required and also a large volume of ultrapure water is needed. This large volume of water is made and stored centrally in a dialysis unit and then put 'online' and delivered to all the machines in a unit. There of course is a financial outlay in setting up a unit to provide olHDF but after that the cost difference is a matter of a few dollars per treatment (or euros) difference (anecdotal evidence). Our understanding of the middle molecule clearance using convective clearance would suggest olHDF should provide our patients better dialysis. Also, recent trials have suggested better outcomes vs standard hemodialysis but there was difficulty delivering high volumes of replacement fluid for each treatment session in some of these trials. See Paul’s RFN post. This team is a new treatment that can potentially improve outcomes for our dialysis patients. For this reason convective clearance reaches the final four for me.

NephMadness 2014 Part 4 - AKI Bracket

In the AKI bracket one team caught my eye, RIPC, Remote Ischemic Preconditioning. This is a procedure of inducing transient ischemia in the arm by inflating a BP cuff for 5 minutes x2 with an interim deflation for 5 minutes. This procedure was done before coronary angiography, aneurysm repair and was shown to reduce myocardial ischemia, renal injury and contrast-induced nephropathy. These procedures have a high prevalence and there are no other therapies to reduce CNI other than fluids (see ACT trial on N-acetyl cysteine), this team is a good contender this year. Hopefully we will see more evidence for this simple procedure. However, my favorite from this group is normal saline, simple, cheap effective, global! How many times has an acute renal failure case, presented to you as a complicated mess by a resident, been solved by some salty water!! I love it! This team goes all the way to the final four for me.

Remember to fill out your NephMadness 2014 brackets! Find them at eAJKD

NephMadness 2014 Part 3 - Kidney Regeneration Bracket

The kidney regeneration bracket is full of heavy weights as usual! However, not being in the field myself one team jumped out for me, Bioartificial Kidney. As the authors of this piece say this is truly the holy grail of nephrology. This field was taken out of the realm of captain Kirk and Dr Spock in 2013 with the publication of reports of a paper in Nature Medicine. In this experiment the authors decellularized a rat kidney a reperfused it with epithelial and endothelial cells. Remarkably this kidney made urine in vitro. The stem cell field was again put under the spot light this year after a publication in Nature by Obokata et al. They reported the discovery of an unexpected phenomenon of somatic cell reprogramming into pluripotent cells by exposure to sublethal stimuli, which they called stimulus-triggered acquisition of pluripotency (STAP). This method basically takes somatic cells puts them in mild acid and they come out as pluripotent step cells! Yes, it sounds unbelievable and it is turning out that way to. Other groups have not been able to reproduce these results using this ‘simple’ technique. Furthermore, the authors have recently submitted an erratum reporting that some images in their manuscript were mistakenly included! Emmm!

NephMadness 2014 Part 2 - Poisons and Toxins Bracket

In the poisons and toxins bracket I learnt some interesting facts. The Dietary Supplement Health and Education Act of 1994 (DSHEA 94) is an example of the power of big business in Washington. Subsequent to acts such as the Nutrition Advertising Coordination Act of 1991 that would have tightened the regulations regarding supplement labeling there was a campaign to exempt supplements and vitamins from the rigorous standards of the FDA. One advertisement featured Mel Gibson being arrested by the FDA for buying vitamin C! On October 25 1994, president Bill Clinton signed the Act into law, saying that "After several years of intense efforts, manufacturers, experts in nutrition, and legislators, acting in a conscientious alliance with consumers at the grassroots level, have moved successfully to bring common sense to the treatment of dietary supplements under regulation and law.” This shocking discovery (for me) made DHSEA go all the way to the sweet sixteen to be knocked out by fomepizole. 

Another very interesting fact was that Glycyrrhizic acid is removed from licorice sold in the US by a process called de-glycyrrhizination (DGL). This eliminates to risk of apparent mineralocorticoid excess (AME). Us Europeans should take a leaf out of the FDAs book!

Please feel free to post a comment on your picks for the poisons bracket!

NephMadness 2014 Part 1- Hypertension Bracket

So it is that time of the year again, NephMadness 2014! I am hoping it doesn’t distract me too much from the basketball… This year’s bracket has thrown up some very interesting match ups. I had a really hard time deciding who goes through in each round. I hope our RFN readers will allow me to indulge myself and do what everyone is told NOT to do in medical school and residency, namely, review a review [article]!

For me the biggest match up was in the hypertension bracket, ACEi/ARBs vs Renal Artery Tx, there was blood on the court! Renal artery ablation was gaining almost legendary status with the potential for it to have a significant impact in the treatment of severe hypertension (SIMPLICITY-1, SIMPLICITY-2). The treatment was safe and would reduce the need for polypharmacy and the associated side effects. Furthermore, with our tried and trusted antihypertensives and ablation therapy, the vast majority of hypertensives could be treated. The early withdrawal of SIMPLICITY-3 shattered all these hopes. This news created a big stir not only in the nephrology community but the whole medical community. Their opponents are also heavy hitters. A member of every family in the western world probably takes ACEi/ARBs! They have had a huge impact in nephrology and the wider cardiovascular population. Even though SIMPLICITY-3 was never completed it was such big news that it dominated the tournament for me and went all the way.

Other big news this year was the long awaited JNC8 report. This had been in the pipeline for years but when it arrived it was not well received by everyone. Some members of the committee even went so far as to publish their concerns about the recommendations. A minority of the panel had concerns about raising the SBP target in over 60s (without DM or CKD) from 140 to 150mmHg.

Please leave a comment telling us about your highlights from this years NephMadness!

The use of Eculizumab in transplantation: What’s new?

Eculizumab is a humanized monoclonal antibody (mAb) that binds the complement protein C5 blocking its cleavage into C5a and C5b, thereby preventing the formation of the C5b-9, the Membrane Attack Complex (MAC).

 Eculizumab is FDA approved for the treatment of paroxysmal nocturnal haemoglobinuria, and for atypical HUS (aHUS). It has been used off-label in the treatment of TTP refractory to plasmapheresis. 

In renal transplant recipients, it has been use, so far, for :
 
    - Treatment of variety of complement/antibody-mediated microangiopathy syndromes such as atypical HUS.
    - Severe antibody-mediated rejection (AMR)/Desensitization protocol;
    - Patients with Antiphospholipid Antibody Syndrome (APS) and its rare subtype, Catastrophic Antiphospholidid Antibody Syndrome (CAPS);
    -To reverse the potentially fatal effects of graft reperfusion injury 
   -To rescue Severe Accelerated AMR in ABO incompatible kidney transplant.

 In lung transplant recipients to treat: 
    - aHUS in combined Lung-Kidney transplant.
    - Hyperacute AMR

In Bone Marrow transplant patients it has been used to treat severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA).

Few important points:

• It is mandatory for patients to be immunized against meningococcus, hemophilus and pneumococci if not current due to the central role of the complement system in fighting infection. Nonetheless, meningococcal sepsis can be seen despite appropriate vaccination. 
• Due to Eculizumab®’s mechanism of action, levels of antibodies-of any kind- are unchanged during its use; therefore researchers are still working to find a way to more accurately measure treatment response. 

** More recently, Lonze and Mongomery’s group at Johns Hopkins used a bioassay as a functional measure of complement blockade and investigated the utility of C5b-9 (MAC) staining on kidney and skin biopsies. They demonstrated on prior studies, that skin tissue is an extremity sensitive site for the detection of C5b-9 deposition. They used normal skin biopsy sites prior to transplant in 3 patients with APS as baseline test. The follow up was done with skin and kidney biopsies. Their concluded that finding a progressive decrement in C5b-9 staining was not useful. Mainly, because it takes several months to almost a year for the tissue samples to no longer demonstrate C5b-9 deposition despite the effective blockade of complement almost immediately after the initial administration of the drug. And, of course, the skin biopsies will only be useful on patients with systemic diseases only. Nevertheless, they successfully transplanted 3 patients with APS, 2 of them with CAPS and highly sensitized. The patients continue to have functioning renal allografts while receiving monthly infusions of Eculizumab indefinitely given their livelong risk of thrombotic events and the poor outcome associated with recurrent CAPS episodes in prior case reports on APS patients with anticoagulation alone.  

Take home messages: 
-Vaccinate patients who potentially will need Eculizumab prior to transplant (at least 4 months). 
- The duration of use is still unclear, but some patients with genetic abnormalities in complement activation may need life-long therapy.
-Adjust dose when using plasmapheresis (redosing after pheresis).
-You may need to do transplant kidney biopsies more frequently to follow up histology in cases of desensitization/AMR since currently there is no other more accurate way to find out if the therapy is working.
- Still no long-term safety data available. Since the variety of complement activation diseases is broad, is not going to be easy to do RTC, and on top of that, placebo arms will be mostly unacceptably in high risk for transplant patients. Nevertheless, large trials are warranted to prove its efficacy and long term safety… stay tune!

Figure from review from Zuber et al. Nat Rev Nephrol 2012

Adela Mattiazzi, MD

Nephmadess is Back

Nephmadness, the renal counterpoint to the NCAA tournament is back again this year. It is being hosted by eAJKD and the new website looks great. I am looking forward to setting my bracket when the tournament starts on March 16th. Go to nephmadness.com to get more details.

Scratching the Surface of Kidney Disease in Sub-Sahara Africa

"John Stanifer is currently a 4th year resident in the Global Health Pathway of the Internal Medicine Residency at Duke and will be joining the Nephrology Fellowship this year. He is interested in first understanding the prevalence of chronic kidney disease (CKD) in Tanzania and then exploring the unique risk factors at play. I asked him to share his thoughts about this region of the world here on RFN so that others can learn from his unique experiences." -Matt Sparks 

I first traveled to Tanzania in 2012 where I realized the enormous need for increased clinical awareness of chronic diseases such as CKD. Global health nephrology may be a new idea for many people, but after practicing medicine and living in Tanzania, the idea has become second nature. It is known that acute kidney injury (AKI) and CKD account for a great deal of morbidity and mortality in this region. As in the developed world, this is not just related to kidney outcomes but importantly impact cardiovascular risk and outcomes. While we do have the capacity for peritoneal dialysis here at the hospital where I work in Tanzania, cost, training, and staff substantially limit its use. The biggest difficulty may actually be in pre-dialysis care. This applies not only to early- to mid-stage CKD but also in the non-dialysis management of AKI. We still have a lot to learn about the nature and impact of kidney disease in developing regions of the world such as Tanzania. We, as a nephrology community, can make a huge impact into helping people cope and potentially prevent kidney disease in a region where little research has been performed.

The United Nations adopted a resolution in 2011 acknowledging the growing global risk of non-communicable diseases such as CKD. In fact, CKD as a cause of death has doubled worldwide since 1990. As such, CKD continues to be an under-recognized burden worldwide. Our recent article in the Lancet Global Health, “The Epidemiology of Chronic Kidney Disease in Sub-Saharan Africa: A Systematic Review and Meta-Analysis” highlights how poor the state of renal research and care is in many low-income countries, and our efforts here in Tanzania are beginning to highlight the disparity between the dearth of data pertaining to renal disease and the magnitude of the problem.

First, we are beginning to understand practice patterns and healthcare utilization among patients with chronic disease such as CKD. Besides cost and access, there are numerous reasons that lead to failure of care for chronic diseases the most important of which may be the lack of understanding of ‘chronic disease’ itself. In a region where untreated malaria is considered the paradigm for ‘chronic disease’, informing patients that their diseases are lifelong and chronic (which often translates as incurable) most commonly results in isolation, fear, and treatment failure.

Secondly, CKD is unique in that it is related to both communicable and non-communicable disease: a point which is especially important in global health nephrology. The well-known and traditional risk factors such as diabetes, hypertension, and HIV are still apparent in this region. However, CKD in this part of the world is also associated with schistosomiasis, tuberculosis, untreated streptococcal infections (structural heart disease from Rheumatic Fever is exceedingly common), environmental contaminates such as lead and arsenic. The most troubling cause of CKD in this region is the pervasive use of traditional or herbal remedies, and one of the goals of our research is to catalogue the remedies that are nephrotoxic and education locals about them.

Third, our preliminary data suggest that the burden of CKD is likely to be as substantial (if not greater) than that of the US and Europe. Alarmingly, we are finding similar prevalence estimates for diabetes, hypertension, and obesity. Crude estimates indicate that the prevalence of CKD is about 12-16% and that diabetes is prevalent in 14-18% of the adult population. In light of these findings, the importance of CKD in the spectrum of non-communicable diseases must be stressed especially in the context of it as a cardiovascular risk factor and in context of the uniform fatality of ESRD in almost all low-income countries. CKD should no longer be viewed as a disease exclusive to the developed world.

After establishing the epidemiology of CKD in the region, our next steps will be to validate measures of renal function, study the genetics of CKD in Eastern Africa, and to establish chronic disease treatment and prevention programs.

John W Stanifer

CJASN eJournalClub: Patient/Provider Characteristics and timing of dialysis start

CJASN’s eJournal Club has recently been revamped with host institutions presenting a chosen article at their hospital on a rotational basis and feeback gathered by the host center. This month’s journal club was hosted by the Division of Nephrology at Duke and concerns a topical and I feel somewhat controversial article. The paper is entitled ‘Provider and Care Characteristics Associated with Timing of Dialysis Initiation’ by Slinin et al. Check out the editorial by RFN’s Andrew Malone at the CJASN website. There will be an ongoing discussion of the paper including author replies to questions posed by the online community. There is a login page but remember registration is free to all (including non-ASN members). The eJournal Club can be a great addition to our online nephrology resources but it requires the participation of the community. Interaction is paramount for its success so your comments are more than welcome.

Dream RCT in Nephrology: what would you choose?

The DreamRCT initiative, driven by Jordan Weinstein of UKidney & Joel Topf of PBFluids, has gone live. The project can be seen as an online reaction to the dearth of clinical trials in nephrology. It has been supported by the nephrology blogging community and features some great ideas to answer burning questions in our specialty. Some dream RCTs are more doable than others but all topics stimulate interest.

RFN has contributed with my IMAGINE & IMAGINARY studies in tranpslant immunosuppression and Andrews DREAM-CARD study of diuretic management after cardiac surgey.



The other enteries are:
O-My Study by Pascale Lane
CA-HIL study by Kenar Jhaveri
URIC ACID-CKD study by Joel Topf
International Glomerular Disease trial network by Matt Sparks
PHANTOM-1 Study by Ed El Sayed
Prevent DeaDD by Swapnil Hiremath
PhosFATE Trial by Jordan Weinstein

Check out the contenders on the impressive UKidney website and vote now. Dream it, do it!

DREAM-CARD. Diuresis Related Endpoints After Major CARDiac surgery

This is my contribution to the Dream RCT in Nephrology poll being coordinated by UKidney. As a nephrologist it seems one spends a lot of time trying to rationalize the use of diuretics in the Cardio-Thoracic ICU. Volume overload and reduction in preload are common and very valid concerns for patients post cardiac surgery. Diuresis to remedy this problem is a physiologically appropriate management strategy. However, as a nephrologist it is not uncommon to see patients that have been diuresed to the point where renal perfusion is compromised. Admittedly this is anecdotal and we see a biased group of cardiac surgery patients. There is evidence that an episode of dialysis requiring AKI in any hospitalized patient increases risk of progression to CKD even if renal function recovers enough for the patient to come off dialysis.

Cardiovascular, renal and survival outcome data for dialysis-requiring AKI in post cardiac surgery patients with relatively preserved pre-op GFR is lacking. It is possible that increased renal outcomes or mortality associated with dialysis-requiring AKI in this group of patients may offset any benefits achieved by cardiac surgeries such as CABG and valve repair. This is the motivation for this ‘dream’ trial. Conducting such a trial would be a very large and difficult undertaking due to the many sources of bias in such a trial and also the fact that blinding a trial involving a dialysis machine is impossible. This would be a very difficult trial to roll out in the real world but here is my best effort!

Inclusion criteria;
Preoperative eGFR over 60ml/min (MDRD)
Elective non-transplant cardiac surgery

Exclusion criteria;
Previous cardiothoracic surgery Macroalbuminuria or greater
Previous AKI events Hospitalizations in the preceding 6 months
Aortic cross clamp time longer than usual as judged by blinded independent panel
Unexpected intraoperative complications as judged by blinded independent panel
Patients requiring RE-intubation after the initial perioperative period (removed from final analysis)

Interventions: The interventions will be randomized into two arms determined by Central Venous Pressure (CVP).
Target CVP: 1) Below 6mmHg versus 2) Below 12mmHg

The approach used to reach this target maybe be determined by the individual clinician. Use of IV Lasix infusion, IV Lasix bolus, concomitant thiazide use or dialysis for the purposes of ultrafiltration (UF) will be documented. Total doses of Lasix and number of days Lasix was used will be documented. Total daily UF achieved by dialysis and number of days on dialysis will be documented. Whether continuous RRT therapy or intermittent therapy was used will also be documented. All the usual demographics and variables will be documented such as serial body weights, urine outputs, blood pressures, serum creatinines and number of days in hospital.

Post discharge patients will be followed. All post surgical hospital admissions and diagnoses will be documented. If patients had elevated creatinines at discharge, serial monthly creatinines will be measured until stable. If patients are discharge home but still on dialysis, the number of days on dialysis before recovery will be documented. The dialysis status of those remaining on dialysis will be followed. All patients will be followed with a yearly creatinine (MDRD). Follow up will be for five years.

The primary endpoint will be mortality
The secondary endpoint will be a composite of renal endpoints including the development of CKD and ESRD.

The goal will be to determine if those who underwent aggressive postoperative volume reduction as assessed by CVP have increased mortality. Furthermore, will those who required mechanical UF to reach their CVP goal have worse renal outcomes?
Remember readers this is a ‘DREAM’ trial, one that is likely never to happen especially as the funding source will be from the large coffers of the RFN! Another major benefit of doing such a trial would be the accumulation of a large amount of useful data.
Vote for DREAM-CARD, badly needed evidence for rounding in the CT-ICU!

Hepatitis B and kidney transplantation

Prior HBV infection is not a contraindication to kidney transplantation. 

It is critical to evaluate patients with serologies and HBV DNA viral load prior to transplant. Most patients should also undergo liver transplant biopsy to exclude significant fibrosis/cirrhosis.
Patients with low risk of reactivation are antiHBc positive and HBsAb positive. Those at higher risk of reactivation have + HBV VL and/or + HBeAg. Those patients with cirrhosis or portal hypertension would benefit of a combined liver/kidney transplant.

The risk of reactivation of HBV under long-term immunosuppression in hepatitis B core antibody-positive, hepatitis B surface antigen (HBsAg)-negative transplant recipients was evaluated over a 3-yr period in 49 transplant recipients (27 liver, 18 kidney, 4 pancreas); 37 recipients (76%) were HBsAb-positive at transplantation (Duhart, Honaker et al. Transp Infect Dis 2003). There was no incidence of HBV reactivation defined as recurrence of HBsAg and/or HBV DNA positivity, suggesting that the risk of reactivation of HBV in hepatitis B core antibody-positive, HBsAg-negative transplant recipients was low with immunosuppression. In the absence of HBsAg positivity, the reactivation of HBV should be assessed using HBV viral loads. 

Do patients with HBV infection benefit from kidney transplantation? 
Recent reports suggest that renal and patient outcomes are comparable to non-HBV infected patients, however, HBV+ patients do carry a 5x fold higher risk of liver failure. Reddy et al. reported no difference in the five-year patient or graft survival between 1346 HBsAg-positive and 74,335 HBsAg-negative recipients who were transplanted between 2001 and 2007 (85.3 versus 85.6 percent, respectively, for patient survival and 74.9 versus 75.1 percent, for graft survival) (Reddy, Sampaio, et al. CJASN 2011).

When should HBV+ patients be transplanted? 
In patients with no evidence of active HBV infection (negative HBV DNA viral load) or cirrhosis/portal hypertension, they may proceed with kidney transplantation. 

How should we manage HBV+ after kidney transplantation?
Prophylaxis with anti-viral therapy is recommended for at least 2 years in order to prevent reactivation. The ideal anti-viral agent is not known though entecavir is commonly used (lower HBV resistance) followed by lamivudine. 
All patients should be placed on a low intensity immunosuppressive regimen, avoiding T cell depleting agents. 
HBV DNA levels should be checked every three to six months to ensure viral suppression and for early detection of virologic breakthrough.

*Patients who are HBsAg neg, anti-HBs neg, but anti-HBc + may develop HBV reactivation after kidney transplantation, but the risk is relatively low. It is controversial whether these patients would benefit from routine antiviral prophylaxis.

Addendum: image from medasend.com

Dialysis in Neonates

Recently, there was an article in Slate magazine that detailed the very difficult decision that had to be made by a pregnant woman who discovered at 18 weeks gestation that her baby had complete bladder outlet obstruction with resulting bilateral megaureters and likely hypoplastic lungs. One of the questions related to the issue of dialysis in a newborn. In the past, this was generally not offered because of the presumption of a very poor prognosis. However, survival in neonates with ESRD has improved and it is becoming more routine in some units to offer RRT. It seems appropriate then, that KI just published a retrospective analysis of dialysis in neonates over the last 15 years.

In total, 254 patients from 32 countries started dialysis before one month of age and about half were in the first week. The most common causes of ESRD were congenital abnormalities of the kidney and urinary tract, cystic kidneys (mostly ARPKD) and cortical necrosis. More than 90% started with PD with most of the remainder starting HD because there was a contraindication to PD (e.g. recent abdominal surgery). One patient had a transplant in the first week but died shortly afterwards. Fifteen individuals had some later recovery of renal function and were able to come off dialysis, at least temporarily.

Overall, survival was excellent - 2-year survival was 81% and 5-year survival was 76.4%. In cases where the cause of death was known, about 2/3 were due to sepsis. Interestingly, the only factor that was significantly associated with an increased risk of death was the presence of concomitant neurological disorders (HR 5.2, CI 1.7-15.4). This may suggest that there was considerable selection bias with neonates who were considered unlikely to survive due to the presence of severe co-morbidities not being commenced on dialysis.

Long term, 45 patients received a transplant in the first 2 years of life. The 5-year patient and graft survival in these individuals was 84.2%.

As expected, there were significant co-morbidities present in these children. 20% had neurodevelopmental delay and 12% had pulmonary problems, mostly hypoplasia (the kidneys are an important source of amniotic fluid which is required for proper lung development). Birth length was below the 3rd percentile in 43% and 63% had growth retardation at 2 years. About 40% were on antihypertensives at 2 years and about 86% required treatment with EPO.

Overall, survival in this very vulnerable group was much better than I would have expected. Of course, given the presence of multiple co-morbidities, it is uncertain what their longer term outcomes would be. However, it does provide some hope to a group who, not so long ago, would have been considered hopeless. Consider that in 1998, a survey of French neonatologists found that 24% would never consider RRT in a neonate whereas a more recent survey suggested that 98% of neonatologists would offer RRT in at least some patients.

CFHR5 Nephropathy and Complement in Kidney Diseases.

It is fair to say that unless you a nephrologist practicing in Cyprus you are unlikely to ever see a case of CFHR5 (Complement factor H related protein 5) nephropathy. It does however give an insight into the growing appreciation of the role of complement in renal disease. The culprit mutation in CFHR5 is thought to affect around 1 in 6000 Cypriots and is associated with autosomal dominant glomerulonephritis and renal failure.

The disease seems to predominantly affects males (why is not well understood) and is characterised by microscopic haematuria with mild proteinuria. Macroscopic haematuria can occur, particularly during episodes of infection. Serum C3 and C4 levels are normal. Progressive decline in renal function leads to ESRD. Biopsy findings are of MPGN with C3, C5 and C9 deposition.

The alternative pathway is both one of the three complement pathways by which C3 can be generated and also provides an amplification loop for C3 generation by the other pathways. Complement factor H is a key regulator of alternative pathway activity. Inherited or acquired deficiencies in CFH can lead to the catastrophic consequences of uncontrolled complement act
ivation seen in aHUS. CFHR5 is also thought to be a regulator of the alternative pathway, though it is probably more important at membrane surfaces rather than in the fluid phase- hence the normal C3 and C4 levels. Defective CFHR5 fails to inhibit accumulation of C3 metabolites at the glomerular surfaces resulting in their accumulation.

CFHR5 nephropathy is one of a group of diseases recently included under the definition of “C3 glomerulonephritis”. These include dense deposit disease, C3 glomerulonephritis and CFHR5 nephropathy. An absence of immunoglobulin deposition differentiates them from immune-complex mediated GN. The C3 glomerulopathies, aHUS, Lupus nephritis, IgA nephropathy, ANCA-associated vasculitis and renal ischemia-reperfusion injury are just some of the diseases where complement is thought play an injurious role.

At present eculizimab –an anti-C5 mAb- is the only licensed complement inhibitor. A large number of other drugs are under development, many of which have other targets in the complement system.

Posted by Jonathan Dick

IMAGINE trial for Transplant Immunosuppression: Dream RCT in Nephrology

I thought I would throw in my two cents on the Dream RCT in Nephrology poll being co-ordinated at UKidney. My choice focuses on transplant immunosuppression and you can see the entry by Joel Topf on PB Fluids here.

There is no standardization of immunosuppression post kidney transplant and before I’m attacked on the blogosphere, I do think that’s a good thing. Each transplant operation is unique with differing immunological risks based on donor & recipient factors. A non-sensitized, white, living donor transplant recipient should be managed different to a deceased-donor, African American, re-transplant. However, there are almost as many different protocols as there are transplant centers and new immunosuppressive agents are becoming available for clinical use. Therefore the transplant community is far from certain which exact agents should be employed for different risk groups. My pick for dream RCT in Nephrology is admittedly a tricky one. If I could have 2 or 3 dream RCTs that would certainly make things easier for me.

Before I start I would like to justify why I feel we need this. The ELITE-Symphony study was a landmark RCT in kidney transplant immunosuppression. Briefly, a regimen of low dose tacrolimus together with MMF, steroids and induction with daclizumab was more beneficial regarding eGFR, allograft survival and acute rejection (AR) at 1 year. Comparison regimens were low dose cyclosporine, low dose sirolimus (both instead of tacrolimus above) plus an additional arm without induction but with standard dose cyclosporine, MMF & steroids. Note that the patients were overall low risk: predominantly white, 35% living donors, mean PRA 20%. This trial solidified the current standard of care for most patients as low dose, triple immunosuppression based around tacrolimus. However since then we have a new kid on the block in belatacept, follow up in SYMPHONY was only 1 year and the issue of induction therapy is not resolved.

Belatacept is a T-cell co-stimulatory blocker and has demonstrated efficacy as a maintenance agent for both standard and expanded criteria donor kidneys. The belatacept studies (BENEFIT & BENEFIT-EXT) used cyclosporine as the comparator and both demonstrated an improvement in eGFR at 3 years despite more early AR.

Let us consider these 2 points which will simplify my imaginary trials:
1. Firstly, no mTOR inhibitors. They’re out! Why do we keep trying to find a mainstream role for mTOR inhibitors in renal transplantation?. I will admit that they have a (limited) role in renal transplantation, mostly when malignancy is an issue or in certain cases of calcineurin inhibitor toxicity (when no proteinuria and preserved GFR). In the ELITE-Symphony study, they had the worst allograft survival & the most adverse events with almost half of patients withdrawing from the sirolimus group. They will never be the cornerstone of immunosuppression post-transplant, especially early post transplant, so they will not be considered.

2. Why is cyclosporine always the control group for new immunosuppressive drugs post transplant? The FDA has traditional mandated that the control arm be a cyclosporine based regimen, despite this not being the standard of care anymore. Tacrolimus is now the leading agent used for >85% of patients as per the SRTR Report 2011 (versus about 4% for cyclosporine). Therefore, cyclosporine is also out. Transplant centers will be more willing to participate as their patients in the control arm will be getting current standard of care.

Immunuosuppression MAnagement for Graft survival IN the current Era (IMAGINE) will be a multi-center randomized controlled trial comparing 2 immunosuppression regimes in general real-world kidney transplant recipients (living & deceased donors, calculated PRA <50%, re-transplants with cPRA <30%). The trial will have a 2x2 factorial design based on 2 induction and 2 subsequent maintenance arms.

1. Induction arm: Basiliximab (daclizumab no longer available) versus rATG. There is an argument for including Alemtuzumab here but this trial is already getting messy so we’ll leave that for IMAGINE-2.
2. Maintenance arm: tacrolimus V belatacept, both with MMF (1g BID)/steroids. It is an open-label design given that belatacept is administered IV and therapeutic drug monitoring is needed with tacrolimus. Maintenance trough levels will be 4-7ng/ml. Note that actual achieved levels in SYMPHONY were close to 7ng/ml despite target being 3-7ng/ml.

Induction: I have included an induction arm as I feel this is another area which needs clarity. For highly sensitized patients there is more consensus that lymphocyte-depleting agents are the way to go (with rATG being more favourable to ATGAM & OKT3). For general low-to-moderate risk recipients, the optimal induction agent is less clear. There is evidence that again rATG is more efficacious but with infection risk and logistical reasons perhaps being important, basiliximab use is common (approximately 1/3 of transplants in 2011).

The sister trial Immunuosuppression MAnagement for Graft survival IN A RiskY population (IMAGINARY) will include highly sensitized recipients with cPRA>50% and re-transplants with prior graft loss due to AR or cPRA >30%. This study will use rATG as induction.

Outcomes: Primary outcome is allograft & patient survival (hard outcomes) at 5 years. Secondary outcome are eGFR and early AR (a relatively soft outcome in my opinion post transplant). Most trials report one year follow-ups which has less relevance for an organ you hope to last >10 years.

Therefore notable features of these trials include hard endpoints, longer follow-up, comparison to the current standard of care and induction arms. That’s my trial design which will form the template for further imaginary studies of newer immunosuppressive agents currently in development. I apologize for the protracted post but these issues couldn’t be dealt with any more briefly! I realize that my dream RCTs may leave me open to criticism but the point of this exercise is to provoke discussion and challenge us to think about what we do and why we do it. And yes, I came up with the trial acronyms before I even wrote the post!

Treatment of secondary amyloid

Recently I've been dealing with an unfortunate individual with a long history of RA who has developed nephrotic range proteinuria after being stable for many years. Despite the deteriorating renal function, NSAIDs have been continued because without them the patient has no quality of life. Biologics were tried in the past with very severe adverse effects and so we are reduced to treating this much the same as it was treated many years ago. Recently, a review in Nature Reviews Nephrology summarized the most up-to-date thinking on the treatment of systemic amyloid. Similar to my patient, about 50% of patients with AA amyloid have nephrotic syndrome and ~10% have ESRD at diagnosis. More than 40% of patients with AA amyloid eventually progress to ESRD.

For AA amyloid, the primary goal of treatment is to suppress the underlying inflammatory disease and hence prevent further amyloid production.

1. Colchicine: Colchicine has been shown to be effective in the treatment of Familial Mediterranean Fever in particular. It is used as a prophylactic agent to prevent the development of renal amyloid and, in higher doses, can be used to treat nephrotic syndrome although care must be used in patients with decreased renal function. There is less evidence for its effectiveness in rheumatoid diseases.

2. DMSO: This has been shown in small studies to be effective in treating secondary amyloid and in murine studies. However, in one study, there was no effect in patients who had already developed significant renal dysfunction.

3. Cytotoxic Therapy: Cyclophosphamide has been shown to have some effect in AA amyloid in small cases series and retrospective studies. There are no RCTs available. One recent study compared cyclophosphamide with etanercept and found that there was a far higher response rate with etanercept. However, this was a small study and was not an RCT so it is difficult to fully draw conclusions. Methotrexate, chlorambucil and axathioprine have also been shown to have some effect.

4. Anticytokine Therapy: This is currently probably the gold standard of treatment. Anti-TNF treatments has been shown to be effective in preventing the development of AA amyloid and even reversing established disease. More recently, in a small retrospective study, toclizumab, a new IL-6 antagonist was shown to be more effective than TNF antagonists in the treatment of AA amyloid. Other anti-cytokine therapies are being tested for their effectiveness in treating secondary amyloid and this is a field that is advancing rapidly.

Warfarin for Atrial Fibrillation in Dialysis Patients: Where’s the data?

ESRD patients have an increased incidence of atrial fibrillation (AF) and a higher risk of stroke compared to patients with normal renal function. However they also have an increased bleeding tendency due in part to uremia and the associated platelet dysfunction. Anticoagulation with warfarin for AF is widespread in the general population, where the sense of risk and benefit are better understood. Like many other conditions, ESRD patients are routinely excluded from clinical trials in AF and therefore we lack hard data on how to manage our ESRD patients with AF. We must rely on observational data, which is often contradictory. Firstly, increased INR variability has been demonstrated in dialysis patients treated with warfarin and they spend much time outside of target INR range. Some registry data supports warfarin use with a suggestion of improved survival in dialysis patients with AF while other studies demonstrate an increased risk of stroke with warfarin [here, here, here]. Overall, the majority of studies do not support a protective effect for warfarin in ESRD patients with AF.

A current study from Canada in Circulation weighs in on the issue. The authors conducted a retrospective cohort study of patients > 65 years admitted with a diagnosis of AF from 1998 to 2007. There were 1,626 dialysis patients (46% received warfarin) and >200,000 non-dialysis patients. In a multivariate analysis, warfarin use in the dialysis patients was associated with similar risk of non-hemorrhagic stroke but a significantly higher risk of bleeding (defined as intra-cerebral, intra-ocular, GI, unspecified hemorrhage & hematuria; HR 1.44). The non-dialysis patients did see a lower incidence of ischemic stroke with warfarin use.

Our ESRD patients comprise a unique cohort with labile, often high blood pressure, repetitive AV access puncture, proven variability in INR and usually anticoagulation use during dialysis. They are certainly high risk for bleeding. Moreover, warfarin use is associated with accelerated vascular calcification in CKD patients and calciphylaxis, an admittedly uncommon but devastating condition. Unfortunately we suffer from a lack of alternatives to warfarin. Accumulation of low-molecular weight heparin in ESRD precludes its use and there is no experience with newer agents such as direct thrombin and Factor Xa inhibitors.
Many authors, including those at UpToDate, recommend warfarin use with AF and an eGFR<15mls/min. They are equivocal when CHADS2=0, but this is rare in a dialysis patient. Remember CHADS2 includes congestive heart failure, hypertension, age ≥75, diabetes and previous stroke/TIA. Despite older age being part of the CHADS2 score suggesting treatment efficacy, age >75 has been associated with a particularly high risk of bleeding in dialysis patients treated with warfarin. Also, CKD is part of the HAS-BLEED score which predicts high risk of hemorrhagic complications to warfarin when the score is ≥3. Many dialysis patients would fall into this category based on hypertension, older age and concomitant meds (85% in the current study in Circulation). I often feel uncomfortable using warfarin in ESRD and certainly feel it should be an individualized patient choice. With the current evidence (or lack of it) to guide us and the significant potential for harm, withholding warfarin for many of our older dialysis patients would not seem unreasonable.

Screening for CKD - The new ACP guidelines - Part 3

Recommendation 3: The ACP recommends that clinicians select pharmacologic therapy that includes either an angiotensin-converting enzyme inhibitor (moderate-quality evidence) or an angiotensin II-receptor blocker (high-quality evidence) in patients with hypertension and stage 1 to 3 chronic kidney disease. (Grade: strong recommendation)

This is the recommendation that I have most of a problem with. The most recent KDIGO guideline on the management of blood pressure in CKD is 85 pages long and although this degree of detail is not necessary for a guideline for general practioners, there is a substantial amount of nuance that has been missed and, in fact, I believe that this recommendation is potentially harmful.

It is clear from many RCTs going back to the 1980s that ACE/ARB therapy is indicated for the treatment of hypertension in all individuals with UACR>300mg/g. Similarly, ACE/ARB are also indicated for all diabetic patients who have a UACR>30mg/g. However, there is no clear evidence that ACE/ARB are preferred in non-diabetic patients with a UACR between 30 and 300 mg/g. The current KDIGO guidelines grade the evidence for the use of ACE/ARB in that setting as 2D (the lowest quality evidence) although there are suggestions from trials that there may be benefit.

However, for non-diabetic patients without albuminuria, there is no evidence that ACE/ARB reduce CVD or mortality relative to other antihypertensives. In fact, there is evidence that ACE/ARB are associated with more complications in non-proteinuric patients (AKI, hyperkalemia etc.) In the TRANSCEND trial the investigators studied the use of telmisartan in patients who could not tolerate ACE inhibitors. Of note, none of the patients had macroalbuminuria although all were high risk individuals. A pre-specified secondary analysis of this study examined renal outcomes and found no significant difference in the treatment group vs. placebo. However, when these patients were separated into those with and without albuminuria, there was a trend towards a benefit in those with albuminuria. In patients without albuminuria, there was an interaction for the main renal outcome (p=0.01) in the direction of harm (HR 2.35, CI 1.33-4.15). This result is not altogether surprising. In my (admittedly anecdotal) experience, the use of ACE/ARB in patients with non-proteinuric kidney disease is hazardous. These patients, usually elderly, are prone to hypotensive episodes and are exquisitely sensitive to volume depletion. the majority have vascular renal disease, even if they do not have clinically significant renal artery stenosis.

It appears that the authors of the recommendation did not take albuminuria into account when formulating this guideline. I would alter it to state that ACE/ARB should be first line therapy in patients with CKD and albuminuria but that they should be used with caution in patients with no albuminuria, particularly in the elderly and those with vascular renal disease. Score this a 0.

Recommendation 4: The ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoproteinn in patients with stage 1 to 3 chronic kidney disease. (Grade: strong recommendation, moderate quality evidence)


This is a pretty uncontroversial statement. Although the benefits of statins in patients with ESRD are no clear-cut, two recent meta-analyses have clearly demonstrated that statins reduce CV mortality in patients with early stage CKD. Score 1.

Overall, I would score these guidelines 2.5/4. Reading around this has certainly highlighted to me the lack of good RCTs to guide therapies that we treat as routine and suggests many avenues for future research although it is difficult at this stage to see who would pay for these studies as they would need to be extremely large and hence, very expensive.