Monday, April 14, 2014

Hepatitis C cure on the Horizon: Implications for Nephrology

You have probably noticed the flurry of articles published this week in the NEJM, coinciding with the International Liver Congress meeting in London, reporting incredible results with new direct-acting antiviral agents in Hepatitis C. This is undoubtedly one of the biggest medical stories of the year and a triumph for science, coming just 25 years after the discovery of the RNA virus. The studies were in patients with genotype 1 HCV although apparently the response is equally as good in other genotypes. The new agents interrupt viral replication which is vital for HCV to exist. Briefly, 2 different regimes have demonstrated sustained viral responses of 94-99% within 12-24 weeks in chronic Hepatitis C patients with and without cirrhosis and with and without previous treatment failures with standard therapy. The agents were administered as once daily in pill form and were well tolerated overall. Ledipasvir and sofosbuvir were the agents in one group of studies and ABT-450, ritonavir, dasabuvir and ombitasvir in the other studies (latter group all had ribavirin; no additional benefit with ribavirin in ledipasvir and sofosbuvir studies).

These new agents have shown spectacular success in achieving a sustained viral response in patients with Hepatitis C and will soon replace standard interferon-based therapy. There is a high burden of renal disease in patients with Hepatitis C, largely glomerular disease (mixed cryoglobulinemia, MPGN and less commonly membranous nephropathy). Treatment of these diseases is primarily directed against the underlying HCV infection. There are many issues with this:

·         Ribavirin is contraindicated at GFR <50mls/min.
·         Pegylated interferon is contraindicated at GFR<15mls/min (with the added issue of assessing renal function in liver patients).
·         Renal transplant recipients who are anti-HCV positive pre-transplant have increased proliferation of HCV, a significantly increased risk of post-transplant chronic active hepatitis, de-novo glomerular disease and may have an increased risk of death.
·         Interferon-alfa is associated with aggressive renal allograft rejection that frequently leads to graft loss, necessitating treatment pre-transplant if at all. Likely mechanisms of this include upregulation of NK cells/cytotoxic T-cells, induction of cytokine gene expression and cell surface expression of HLA antigens.

For nephrologists, we want to know what role these agents will have in our patients. The first issue to note is that all these studies excluded patients with a creatinine clearance <60mls/min (as per Cockcroft-Gault in ABT-450 based studies; unknown method in the ledipasvir/sofosbuvir studies).
As per the manufacturer, sofosbuvir has never been studied in patients with a creatinine clearance <30mls/min. However, a trial is underway examining its use in this population. I could not find any data on the other agents regarding renal function.

The incredible results of these studies should have beneficial knock-on effects for nephrology, including a lower incidence of HCV-related nephropathies, the ability to treat patients post-transplant and maybe even less demand for combined liver-kidney transplant. However, some uncertainty remains particularly regarding how to use these agents in CKD/ESRD and predictably, economics. Estimated treatment costs of $90,000 will preclude many in the developing world, in particular, from accessing these curative agents. We await with interest how the story progresses from here.

Monday, April 7, 2014

The use of Rituximab in Kidney Disease

Rituximab, the monoclonal chimeric anti-CD20 antibody, is an effective B-Cell depleting agent and continues to gather data for its use in a wide range of conditions relevant for the Nephrologist. It was also a pre-season favourite in the recent NephMadness event run by our friends at eAJKD, so I figured a quick recap was timely. As the literature is vast and grows by the week, I will only give a brief review of the current data, much of which is weak consisting of small observational reports.

Lupus Nephritis
The jury is still out. The LUNAR study randomized 144 patients with proliferative LN to Rituximab 1g x 4 or placebo with both groups receiving MMF & steroids. The experimental group had a decrease in anti-dsDNA and complement levels. Remission rates were numerically, but not statistically, better with add-on Rituximab (57% V 46%). While a lack of benefit with additional use of Rituximab was demonstrated, whether it could be an alternative to MMF is not known. In cases of resistant LN, we again have multiple favourable case series but no hard evidence.

Steroid-Resistant Nephrotic Syndrome (SRNS)
Evidence suggests Rituximab may be effective in steroid-dependent or calcineurin inhibitor-dependent patients, allowing withdrawal of one/both agents. An open-label RCT in 54 children with SRNS examined standard therapy (with steroids & calcineurin inhibitors) to Rituximab with lowering doses of usual therapy. The experimental arm had lower proteinuria, less relapse and was more likely to be drug free at 3 months. However, relapse did occur in 18.5% of Rituximab treated patients at the time of recovery of the B-Cell population.
The data does not all demonstrate a benefit however, which brings us to a recent small case series in the NEJM. Another anti-CD20 monoclonal antibody, this time the humanized preparation Ofatumumab, was reported to be an effective treatment in 5 cases of SRNS refractory to Rituximab. Although both are anti-CD20 antibodies, they have different epitope specificities which may explain the outcome in this small series. This reinforces the idea that B-Cell depletion is more complex than some may presume.

Minimal Change Disease
No RCT data exists but observational series suggest a benefit in steroid-dependent, but not resistant cases. A new case series in NDT reports on 16 adult patients with MCD who were steroid-dependent (n=12) or resistant and given 2-4 doses of Rituximab. Overall, 13 had a complete and 2 a partial remission with one non-responder. No serious adverse events were reported but 7 relapsed after 9–28 months.

Membranous Nephropathy (MN)
Guess what? No RCT data exists but limited data suggests it may be a useful agent. (See Nate’s previous post). The largest observational study I could find included 100 patients, 32 of whom had disease resistant to other immunosuppressive agents. Baseline proteinuria of 9g/day had been present for a mean of 2 years. Complete/partial/no remission was achieved in 27/38/35 patients respectively, remissions after a mean of 7 months. Prior immunosuppressant use did not appear to alter outcome. Other smaller studies also report that patients, including those with resistant disease, may respond.
There is evidence that Rituximab may cause a decrease in Anti-M-type Phospholipase A2 Receptor (PLA2R) antibodies. In this study, 25/35 patients with idiopathic MN had Anti-PLA2R antibodies, and these autoantibodies declined or disappeared in 17 (68%) of these patients within 1 year of rituximab treatment. The patients who demonstrated antibody response had much improved rates of complete and partial remission in this small study. Perhaps these autoantibodies may prove to be a useful biomarker for treatment response in MN.

ANCA associated vasculitis (AAV)
As per the RAVE study (& RITUXIVAS), there is now robust evidence that a 4 week course of rituximab is non-inferior to cyclophosphamide in the treatment of AAV, including a finding that it may be superior to conventional immunosuppression in relapsing patients. Note that only 2/3 of patients had renal impairment in RAVE with creatinine clearances of 54-69mls/min in the 2 groups. See my previous post for more detail.

Limited evidence suggests it may be beneficial in steroid-dependent but not steroid-resistant cases. We must be wary of publication bias from early series which reported  positive findings, especially as they have often failed to be replicated. It has been used with some success for recurrent FSGS post-transplantation, often together with plasma exchange. There is growing evidence for a direct effect on the podocyte, as well as its known anti-B Cell effect, possibly via binding of podocyte proteins such as SMPDL-3b.

It is beyond the scope of this post to delve into the use of Rituximab in transplantation. It can be used in desensitization protocols, PTLD and treatment of acute antibody-mediated rejection (AMR) as adjuncts to IVIG and plasma exchange (trial data awaited regarding allograft outcome). There is no clear evidence for its use in chronic AMR, which tends to have little response to any agent.

Another indication is essential mixed cryoglobulinemia. Here, Rituximab has been reported to be beneficial in cases usually associated with Hepatitis C infection. See Gearoid’s previous post.
Overall, B-Cell depletion in general is an exciting treatment strategy for many of the disease processes we deal with. Like much in Nephrology, we lack strong data for if, when and how to use it. We also lack thorough knowledge as to its precise mechanism of action. Suggestions of a direct podocyte effect in glomerular disease and different mechanistic effects of alternate anti-CD20 preparations illustrate how much we have to learn.

Friday, April 4, 2014

Perils of Estimating GFR in Patients with Cirrhosis

In my attempt to highlight nephrology content in non-renal journals, I will this month focus on a series of articles in Hepatology concerning eGFR in cirrhotic patients. We are all aware of the concerns using creatinine-based tools for estimating GFR in this patient cohort given their malnourished, low muscle-mass state. The use of Cystatin-C based equations may theoretically be more informative as this protein is not influenced to the same degree by non-renal factors. However, Cystatin-C is far from perfect and is influenced by sepsis, inflammation and steroid use. Other concerns include the use of the MDRD-6 equation due to the inaccurate determination of albumin (may receive IV infusions) and urea (increased by GI bleed/steroids) in these equations.

As liver patients with renal dysfunction have such a poor prognosis, they are prioritized for liver transplant by way of inclusion in the MELD score, the prognostic tool used to allocate liver allografts. Since adopting MELD, the number of combined liver-kidney transplants (cLKT) has continued to grow, with cLKT considered when GFR<30mls/min and sometimes at higher eGFR. As the demand for kidneys continues to outstrip supply, nephrologists in particular have legitimate concerns regarding the potential for inappropriate use of precious renal allografts in cLKT. This may occur if eGFR underestimates true GFR as may occur with creatinine-based equations. Also concerning is overestimation of true GFR resulting in denial of cLKT where it may actually be indicated, leading to inferior patient outcomes. (See the post by Andrew regarding combined liver-kidney transplant allocation).

Francoz et al studied 300 patients with cirrhosis being evaluated for transplant that had iohexol clearance measured. This was compared to MDRD-4, MDRD-6 and CKD-EPI equations (all using creatinine only) and found that MDRD-6 was the most accurate although it did underestimate true GFR and all 3 equations had poor correlation (R2 0.37-0.4). MDRD-4 and CKD-EPI overestimated GFR especially in those with GFR<60mls/m.

DeSouza et al also looked at patients being evaluated for transplant (n=202) and measured GFR using inulin clearance. Throughout all severities of cirrhosis, Cystatin-C equations were superior with CKD-EPI (Cys-C) the best, compared to creatinine-based MDRD & CKD-EPI methods (which significantly over-estimated true GFR). Of note it outperformed CKD-EPI (creatinine-cystatin-C combined).

Mindikoglu et al examined 72 outpatients with stable cirrhosis comparing CKD-EPI (creatinine-cystatin-C combined) to 24-hour creatinine clearance, Cockcroft-Gault equation and multiple other creatinine-based methods including MDRD & CKD-EPI. Their gold standard was iothalamate clearance. CKD-EPI (creatinine-cystatin-C) performed better than all others including CKD-EPI (Cys-C), unlike DeSouza et al.

Confusing right? What we can take away from these useful studies is that Cystatin-C based equations may be better than creatinine alone equations (remember Francoz et al did NOT use Cystatin-C). However, it should be noted that the diagnostic performance of the best equations in the studies was still markedly lower than reported in validated normal populations. 
My feeling is that in borderline cases when a cLKT is being considered, we need additional data. I would consider a borderline case stable renal dysfunction in the eGFR 20-50mls/min range (arbitrary I know!), not including co-existent ESLD/ESRD or obvious acute hepatorenal cases which will recover with a functioning liver allograft. As renal biopsy is usually not desirable in patient with chronic liver disease, it seems sensible to actually measure GFR in these cases. This appears to be the prudent approach to take to strike a balance between providing a kidney to those who need it and not inadvertently denying an organ to a wait-listed ESRD patient.

Monday, March 24, 2014


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:

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!

Sunday, March 23, 2014

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!

Saturday, March 22, 2014

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 they 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 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.

Friday, March 21, 2014

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!

Thursday, March 20, 2014

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!

Wednesday, March 19, 2014

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

Tuesday, March 11, 2014

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 to get more details.

Wednesday, February 26, 2014

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

Tuesday, February 25, 2014

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.

Tuesday, February 18, 2014

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!

Monday, February 17, 2014

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!

Sunday, February 9, 2014

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