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.