Top nephrology-related stories of 2016

2016 marks the 7th year of the Top Nephrology Stories post on RFN. When this list first started in 2010 it was more challenging to get the stories. Now 7 years later, everything has changed. In my mind the advent of Twitter and NephJC has changed all of that. We are more informed and better read on nephrology topics. All you need to do is go over to NephJC and look at what is being talked about. Everything is there. Discussion is deep and constant.

Announcement:

• NephJC will host the #TopNephrology stories starting in 2017. 
• We will use analytics from each of the chats throughout the year plus feedback from the NephJC team to create a #TopNephrology list. 

We hope these changes will result in an improvement and reflect the Top 10 stories that you need to be aware of. RFN is not going away and we have big plans for RFN. If you are a fellow and interested in posting to RFN please send me an email or DM.

Below are links to the last 6 years of the top nephrology stories hosted on RFN.

2010
2011
2012
2013
2014
2015 

10. HLA-incompatible live kidney donation survival benefit in NEJM (5%)- Coming in as a tie for number 10 is a study reported in NEJM (March 2016) and covered by NephJC. It is well known that kidney transplantation is the best form of renal replacement therapy. However, there is a limited number of organs to meet the growing demand. Furthermore, patient related factors such as the presence of anti-HLA antibodies are another factor lengthening the wait time and often preventing transplantation. This study looked at matched patients (not a randomized trial).

• One group of kidney transplant recipients undergoing a desensitization protocol with a live donor incompatible kidney transplant

versus

• A matched group who underwent deceased donor kidney transplant with a match or remained on the wait-list. 

The study looked at multiple kidney transplant centers between '97-'11 The results were striking. Patients who underwent a live incompatible kidney transplant with desensitization protocol had a significant survival advantage compared to wait-listed patients and wait-listed + deceased donor. However, it must be noted that the desensitization protocol itself has side effects and careful consideration is needed before using this method. This study is important because it represents a significant advance in generalizing the use of desensitization for patients unable to obtain a kidney transplant because of preformed antibodies.

10. ELAIN Trial of early versus late HD in the ICU in JAMA (5%)- This spring started off with a bang. Back to back presentations of renal replacement therapy in the ICU showing different results. First the AKIKI Trial (our number 3 story) was presented at the Critical Care meeting in San Diego and reported in NEJM and showed no difference in early versus late. A few weeks later came the ELAIN (Early vs Late Initiation of Renal Replacement Therapy in Critically Ill Patients With Acute Kidney Injury) Trial. This was a single-center randomized trial presented at the ERA-EDTA Congress in Vienna, and reported in JAMA. They found a significant reduction in 90-day all-cause mortality in the early initiation group. Some important caveats.

1. This was a single center study (AKIKI was multicenter).
2. Majority of patients were surgical ~80% (AKIKI ~80% medical) 
3. 100% were CVVHDF (AKIKI ~30% CRT) 
4. Only 4% in late group avoided RRT (~50% in AKIKI). 

Bottom line- these were very different studies and hence had very different results. Could a select group of patients with a more defined ischemic insult benefit from early RRT in the ICU? Jury is still out but the ELAIN Trial would suggest this to be true.

9. EuLite Trial of high cutoff dialysis in myeloma presented at UK Kidney Week (6%)- The long awaited results from the EuLite Trial were presented at UK Kidney Week this year. See Paul Phelan's post on RFN from way back in 2013. Unfortunately, the EuLite Trial isn't published just yet so we have is the live Twitter coverage from the meeting. The premise is that High Cutoff (HCO) Dialysis would provide benefit from removing toxic free light chains in myeloma cast nephropathy. HCO dialyzers employ high flux membranes with particularly large pores (up to 50kDa Vs 15kDa for conventional high flux) facilitating the removal of large plasma proteins such as FLC (kappa and lambda light chains have molecular weights of 22kD and 45kD respectively). The EuLite Trial is a randomized clinical trial testing the use of HCO dialysis versus standard dialysis  in patients with myeloma case nephropathy. Unfortunately, HCO Dialysis arm of the study had more mortality compared to the standard HD arm hinting at harm. We all eagerly await the full publication to be reported to we can really delve deep into this study. Looks like the early enthusiasm for HCO dialysis in myeloma cast nephropathy is fading as well.

7. Contrast nephropathy study in JASN (8%)- September brought a bombshell of a study. The Wilhelm-Leen, Montez-Rath and Chertow paper looked at the risk of acute kidney injury in the days following a dose of radiocontrast. And the researchers could find no hint of AKI. To say this counters nephrology dogma is an understatement. If Moses had brought down the Nephrology Ten Commandments, Thou shalt avoid radiocontrast would probably be in the top three, following only by Thou shalt monitor and control one’s blood pressure and Thou shalt not eat so much salt. The investigators used NIS, the largest publicly available all-payer inpatient care database, this covers 96% of the US population and used diagnosis and procedure codes to find exposures and acute kidney injury. Despite that limitation the result is so provocative that it begs relooking at this toxicity with open eyes. Of note similar findings have been published in the radiology literature for years: McDonald JS, Bruce RJ, while others have upheld the orthodoxy.

7. "Fistula First" survival benefit is due to patient factors in JASN (8%)- If contrast nephropathy is really just a figment of confirmation bias, then at least we know that fistulas are the best hemodialysis access and convey a true survival benefit. Or maybe we don’t know that. The same issue of JASN brought us the work of Robert Brown, Bhanu Patibandla and Alexander Goldfarb-Rumyantzev. The thread that triggered this investigation was the repeated observation that every study that revealed a survival benefit for starting with a fistula (all observational and retrospective data) also showed that catheter patients were different from patients starting with a fistula. Often the catheter patients were older, more urban, shorter pre-ESRD nephrology care, more diabetes, more cerebrovascular disease, and more heart failure that the patients starting with a fistula. The authors looked for a way they could separate fistula patients from these inherent biases that could explain the survival benefit these patients enjoyed. The authors divided elderly new starts to hemodialysis into three groups:

1. Started dialysis with a fistula 
2. Started dialysis with a central venous catheter, but had a fistula that was maturing when they started dialysis 
3. Started dialysis with a central venous catheter 

If the fistula was driving mortality, group 2, that is dialyzed with a catheter, should have outcomes similar to group 3. If the patient characteristics were driving the survival advantage of the fistula, group 2 should look like group 1.

The money quote from the conclusion

although this study has confirmed the approximately 50% decreased mortality experienced by patients initiating hemodialysis with an AVF compared with a catheter, it showed that about two thirds or more of this mortality benefit is also seen in those initiating hemodialysis with a catheter but who had previously undergone unsuccessful fistula placement. Thus, these observational data suggest that the actual mortality attributed to the catheter itself is much less than previously considered and may be explained in large part by differences in patient factors. 

Similar conclusions were published in JASN this October using Canadian data. That team is planning on confirming these results with a randomized controlled trial of fistulas versus catheters (see this Medscape article, log in required). That will be amazing!

6. US Congress expands Medicare coverage for acute dialysis coverage (10%)->In June of 2015 the nephrology world suddenly became very interested in the Trade Preferences Extension Act of 2015. Because politics is hard, an important bill for acute kidney injury got stapled to this larger "Transporter bill". On June 29th President Obama signed the bill and section 808 became law.

Specifically, Section 808 of the law amends the Medicare statutes to provide coverage for “renal dialysis services furnished … by a renal dialysis facility or provider … to an individual with acute kidney injury.” 

This overturned a CMS ruling from 2012 that forbid medicare reimbursement to dialysis providers for the condition of acute kidney injury. This left lots of patients in a lurch. Patients unfortunate enough to develop AKI often would recover from their acute illness but they would have to remain in, or close to, the hospital as their acutely dtysfunctioning kidneys recovered or didn’t. Until a nephrologist was willing to give up hope and declare the patient ESRD, that patient would not be able to receive dialysis anywhere but the hospital. This esoteric bureaucratic red tape of where and when people could get dialysis hurt patients and it is nice to see this straightened out, even if it was passed in 2015 and doesn’t go into effect until January 1, 2017.

5. Nephrology societies embrace social media (11%)- Most of the nephrology societies have had a social media presence for many years (see this Twitter list from Joel Topf) however, 2016 marked some sort of a watershed in the seriousness, enthusiasm and effort taken by many of them to really engage with social media.

The American Society of Nephrology (ASN) has a very active Twitter presence, and actively tweets out the latest breakthroughs in research and other news in the nephrology universe. Along with ASN Kidney News and ASN Advocacy, the two flagship journals, JASN and CJASN, also have active Twitter handles, and are progressively using the medium effectively for communication. But two other initiatives stand out in all the things the ASN does on social media this past year: #askASN and ASN communities. Once every month, the ASN brings forward an expert for the #askASN chats (some of the featured guests include Richard Lafayette who runs Kidney News, POTASN Ray Harris and PEOTASN Eleanor Lederer, KidneyWk organizers Roy Zent and Patrick Nachman, and SPRINT investigators George Bakris and Bill Cushman) to answer questions from the nephrology Twitterverse. Secondly, a few months ago, spearheaded by Zachary Cahill, the ASN launched a forum, ASN Communities. It has gathered steam, and now boasts 8 separate communities (the Open Forum and Patient Care being most active, with Onconephrology, Transplant, AKI, Basic Science, Supportive Care, Training Program Directors being the others), with over 3,000 discussion threads!

The ERA-EDTA has been on Twitter for a while, but they publish two journals, and until recently didn’t have a social media presence. But they stepped nicely to a request, and @NDTsocial and @CKJsocial were born. Both have been actively tweeting out snippets of the latest nephrology literature (with CKJ continuing to be an #openaccess journal) over the last year.

The International Society of Nephrology (ISN) is ramping for the upcoming World Congress of Nephrology, scheduled to be held in Mexico in 2017. The ISN does have an active education committee and holds regular webinars, but for the WCN, they have established a WCN 2017 social media task force make up of 20 nephtweeters from around the world. We look forward to their coverage of the WCN2017.  Now only if someone could persuade Kidney International to join Twitter…

The National Kidney Foundation (@NKF) is also active on Twitter and actually sets the record for number of followers ~19,000. The NKF Spring Clinical Meeting (@NKFClinicals) was much more active this year and featured a live social media workshop. Next years meeting is featuring a social media ambassadors program at SCM17. Of course AJKD was an early adopter of social media and a leader in the space with AJKD blog,  NephMadess, and AJKDonline Twitter handle.

4. Empagliflozin approved for CV indication by FDA (13%)- A common refrain in the diabetes literature has always been a lack of benefit seen for hard outcomes with hypoglycemic agents, with metformin being a lone exception. This all changed with the EMPA-REG trial, which made it to the #TopNephrology stories in 2015 as number 2. At that time, we just had the late breaking trial to work on, but it was already huge news. The subsequent publication in NEJM was covered at a #NephJC session too. The need for this trial to be done is very interesting – until recently, showing a drug lowers blood sugar was the most important aspect of getting FDA approval. After the debacle behind rosiglitazone (avandia) and the possible risk of greater cardiovascular events despite lower blood sugar, the FDA mandated larger trials to demonstrate CV safety. EMPA-REG was one such trial, and demonstrated remarkable benefit in lowering CV outcomes. The FDA followed suit, and on Dec 2 announced a new indication for empaglifozin – for reducing cardiovascular death in patients with type 2 diabetes. The SGLT-2 inhibitors have indeed come a long way in a short period of time.

3. AKIKI Trial of early versus late dialysis in the ICU in NEJM (20%)- Coming in at #3 in this years poll is AKIKI. AKIKI was also the winner of the #NephJCKidneys at KidneyWk for Study of the Year. The timing of renal replacement therapy has been rated as a top priority for research in the AKI world. Indeed, in the last few years, clinical practice has slowly crept ahead of evidence, as it often does, and dialysis is being initiated earlier and earlier for acute kidney injury. And then came along the Artificial Kidney Initiation in Kidney Injury (AKIKI) trial, to do what IDEAL did for timing in the chronic dialysis field. In this trial, 620 patients with AKI were randomized to either early strategy (with RRT initiation at stage 3 AKI per KDIGO criteria) or delayed strategy, when a clinical indication occurred (eg hyperkalemia, pulmonary edema, or persistent oliguria > 72 hours). There was no difference in mortality, with only half the patients needing dialysis in the delayed group, who also had significantly less bloodstream infections. Check out the #NephJC coverage for more details.

2. PPI and CKD risk in JAMA Internal Medicine and JASN (22%)- This was big. Another important paper dropped in nephrology literature during springtime. We had AKIKI, ELAIN and now PPI causing CKD all Feb to April. The PPI leading to CKD story was first reported in JAMA Internal Medicine then in JASN. NephJC covered this and you can view the background and both chats here. While a rare association between PPI use and interstitial nephritis has been known for a while. Their association with chronic kidney disease had not been reported before. The JAMA Internal Medicine paper is an observational, prospective cohort study with two cohorts. The first is the Atherosclerosis Risk in Communities (ARIC) study, of which 10,482 participants were included. The second was the much larger Geisinger Health System Replication (GHSR) Cohort, with 248,751 participants. Participants using either PPIs or H2 antagonists were compared with each other to evaluate their respective risk of developing kidney disease. A propensity score-matched analysis was conducted to minimize confounding variables and identify whether baseline PPI use was associated with CKD. It is important to note that PPI users in both cohorts were more likely to have a high BMI, hypertension, cardiovascular disease, and exhibit polypharmacy (with antihypertensives, aspirin, diuretics and statins). They found that PPI use is associated with a higher risk of incident CKD. The JASN paper from Xie et al used a Department of Veterans Affairs national databases to build a primary cohort of new users of PPIs (173,321) and new users of H2 blockers (20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR decline less than 60, incident CKD, and a graded association between PPI duration and risk of renal outcomes. Both of these studies point to a fundamental issue in medicine. Polypharmacy. We need to remain vigilant to remove medication that have no clear indication. PPIs once thought of as innocuous now have real risk associated with them.

1. suPAR from bone marrow myeloid cells in Nature Medicine (64%)- Coming in at # 1 this year is a basic science paper just published a few weeks ago in Nature Medicine. Just like the Gli1 story of 2014 we will also have to add an asterisks to this win. The suPAR aficionados really came out in force with heavy voting and it is not a surprise for us as suPAR has been a consistent story for the last 7 years. suPAR graced the TopNephrology stories in 2011. In fact, it hit the number 1 spot with the original Nature Medicine paper describing its potential link to FSGS. Then in 2015 suPAR was unable to crack the top 10 and landed at number 14 with the NEJM paper linking suPAR to CKD in a cohort of patients at Emory undergoing cardiac catheterization. Now in 2016, suPAR does it again. Our #1 story. The current study seeks to identify with cellular source of soluble urokinase plasminogen activator receptor (suPAR) which the above studies have implicated in CKD. Most notable is the fact that if a patient with FSGS receives a kidney transplant unfortunately their is a high chance of recurrence. Thus, implicating an extra renal "factor" like suPAR leading to kidney damage. Utilizing a combination of bone marrow chimera, ablation and cell transfer studies that suggest that Gr-1lo immature myeloid cells of bone marrow origin is the source of suPAR and a key contributor to glomerular damage. A very interesting observation that will no doubt lead to more studies on the link between bone marrow derived cells and kidney function.

Another busy and exciting year in the world of nephrology in 2016. Thanks to all of the contributors and readers in the nephrology online community for keeping nephrology fun, interesting and educational. Next year the #TopNephrology stories will be moving to NephJC.

Thanks for supporting RFN and NephJC. Happy holidays from the entire team.

Can't wait to see what 2017 has in store!

Don't forget to sign up for the NephJC email to keep up to date

Post by Matt Sparks, Swapnil Hiremath, and Joel Topf

Top nephrology-related stories of 2015

What a year 2015 turned out to be. Nephrology social media is beginning to mature with many projects adding to a rich educational experience online. Who needs MOC when you have this! NephJC continues to be one of the most successful online journal clubs in medicine. NephJC is also a great resource to look back at the landmark trials, guidelines and papers. What happened in nephrology during 2015? Without a doubt SPRINT dominated the internet but we also had some good news with kidney endpoints using SGLT2 inhibitors in diabetes. Some familiar faces reappeared (tolvaptan, saline, patiromer, ACEi) and new stories emerged (hep C Rx, SGLT2 inhibitors, IgA Rx). Overall, 2015 proved to be an exciting year in nephorology.

Below are links to the last 5 years of the top nephrology stories. Hard to believe that this is the SIXTH year of Top Stories! Maybe we can do a top stories of the decade soon!

2010
2011
2012
2013
2014

10. ACEi in kidney transplant did not modify outcomes reported in The Lancet Diabetes and Endocrinology (22%)- A long held belief in nephrology is that Ang II blockade helps anything kidney related, especially if it has to do with proteinuria. Multiple studies have demonstrated this effect in non-transplanted patients with proteinuric kidney disease. Enter this study by Knoll et al. published in The Lancet Diabetes and Endocrinology. This was a randomized trial performed in Canada and New Zealand where 213 patients with eGFR greater than 20 with more than 0.2g/24 hours of proteinuria were randomized to the ACEi ramipril 5mg BID (104 patients) versus placebo (109 patients) for 4 years. Primary outcome of doubling of Creat, ESRD, or death. The primary outcome was similar between both groups (~17% placebo vs ~14% ramipril). Furthermore, there was no difference in decline of eGFR (sec. endpoint) between the 2 groups. Lastly, there were more AEs in the ramipril group. There you have it. ACEi did not modulate clinical outcomes in patients with a kidney transplant and proteinuria. Maybe this is because the pathophysiology of proteinuria in kidney transplant is not driven by Ang II.

9. C-SURFER trial of anti-HCV Rx in CKD reported in The Lancet (26%)- Just unbelievable what has happened in the world of hepatitis C treatment. Hepatitis C infection was once considered a devastating disease. Treatment consisted of ribavarin and interferon and was awful to take. Patients hated it and to make things worse it only results in sustained virological response in 60-70% of patients. Not to mention the difficulty encountered in offering this therapy to patients with CKD. This all changed in 2014 with the publication of 3 trials demonstrating remarkable efficacy and tolerability of antiviral drugs for hep C treatment (here, here, and here). What about patients with CKD? This was tackled in the C-SURFER study published in The Lancet and reviewed on RFN by Praveen. This study was a randomized study evaluating the efficacy and safety of grazoprevir and elbasvir (GZR/EBR) in genotype 1 HCV with stage 4 or 5 CKD including patients on dialysis (n=224). 76% were on dialysis! The results were impressive. 99% of patients achieved an SVR with minimal toxicity. This is truly a game changer. Can't get through clinic now without seeing a few patients on this therapy now.

8. The approval of tolvaptan (jinarc) in UK and Canada for ADPKD (27%)- The Tempo 3:4 trial was top story of 2012. This trial showed that treatment of ADPKD with the vasopressin antagonist tolvaptan slowed the increased in total kidney volume and the decline in kidney function. The next year (2013) tolvaptan of ADPKD made the top stories list again. This time at number 6 for failure to gain approval from the US FDA. Commonly cited reasons are the lack of hard endpoints (ESRD) and liver toxicity. However, earlier this year Canada (see this post from UKidney) and the UK approved tolvaptan (labeled as jinarc) for ADPKD. We will see where this story goes in the US.

7. SPLIT trial showing buffered crystalloid not different than saline in reducing AKI reported in JAMA (31%)- Another story that came back in '15 was the battle between buffered crystalloid and saline in the ICU. This made an appearance in the 2012 top stories as number 7 (ironically same this year) with a study that rocked the saline world. Again, published in JAMA and showing that fluid resuscitation with chloride restrictive solutions had less AKI and need for dialysis. The battle carried over to NephMadness '14 which featured a massive first round defeat for normal saline. Read this Skeptical Scalpel post on the subject. Enter the SPLIT trial. Both buffered crystalloid and saline were at it again as fluid resuscitation in the ICU setting. The trial was based in New Zealand and had over 2000 patients as compared to ~700 in the earlier paper. However, the results were not the same in these two studies. The SPLIT trial showed that the rates of AKI and dialysis use in AKI were similar between the two groups. Thus, vindicating normal saline, who was starting to earn a bad reputation. Questions still abound in particular to high risk patients. Looks like a win for normal saline this time around.

5. PATHWAY-2 Trial showing spironolactone effective in resistant HTN reported in The Lancet (33%)- Spironolactone seems to be the nephrology darling. Always making a pleasant appearance. Blocking the mineralocorticoid receptor was in full force in '15. The PATHWAY-2 trial did not disappoint. This was a study published in The Lancet and dutifully covered in NephJC that tested spironolactone as add on therapy in resistant hypertension. The study was performed in the UK and was a 1 year double blind placebo controlled trial that pitted spironolactone vs. doxazosin vs. bisoprolol vs. placebo plus usual care. Spironolactone was the clear winner without alot of AEs. Take a look at the NephJC storify which sings the praise of spironolactone.

5. First in-human use of Wearable Artificial Kidney (WAK) for 24hrs presented at ASN Kidney Week (33%)- The wearable artificial kidney (WAK) has been in and out of the nephrology literature over the last 5-10 years. My first introduction to the WAK was by Nate Hellman in 2008. Since the original description in 2007 (spearheaded by Victor Gura) the WAK makes an occasional appearance at ASN Kidney Week. This year the WAK made a splash again. This time the WAK was tested in a group of 7 individuals for a total of 24 hours. Before this the study the WAK was only used for 8 hours. The story made big headlines and was reported on CNN. The results weren't all perfect. 2 of the 7 patients had to stop wearing the WAK because of malfunction. What will happen to the WAK in the future and is the a practical solution to ESRD? We will see what happens next.  

3. STOP IgA presented at ERA/EDTA and ASN Kidney Week 2015 reported in NEJM (34%)- For me one of the surprising publications this year was the STOP-IgA trial. This was not surprising because of what it showed but because I was not expecting more data on IgA nephropathy. IgA Nephropathy is one of those diseases riddled with case studies. IgA nephropathy can lead to substantial frustration for both the patient and the physician. There is a subset of patients where immunosuppression (IS) is no doubt warranted such as rapidly progressive kidney decline or in cases of crescentic IgA nephropathy. What is not clear is the middle ground. patients with proteinuria in 1-3g range. What do you do with them? The STOP IgA study was performed in Germany and had a 6 months run in phase consisting of mainly RAAS blockade. About 1/3 of the 309 enrolled patients were excluded because they had a response during this run in phase. This left only 177 patients to be randomized to either supportive care alone or IS (prednisone for high eGFR and cyclophosphamide followed by Aza for 6 months in the moderately depressed eGFR). After randomization they were followed for 3 years. They found that the addition of IS resulted in more patients in full clinical remission. However, there was no difference in the co-primary endpoint of eGFR decrease. In the end, the results indicate that IS on top of supportive care really didn't add much. Check out the coverage at RFN by Andrew McClarey and over at NephJC. More evidence to add to our guidelines.

3. FDA approval of patiromer (veltassa) for hyperkalemia treatment (34%)- This year marked another landmark in nephrology. The FDA approval of patiromer (marketed as veltassa) represents a new era in therapy for hyperkalemia. The makers of veltassa, Relypsa, announced just this week that the drug is now available for prescription. There have been several high profile papers in regards to this drug. However, all have been placebo controlled. The AMETHYST-DN trial looked at patiromer in patient with diabetes and hyperkalemia and showed that over a 52-week time period the drug resulted in decreased potassium levels. Adverse effects were modest and were low Mg, K, constipation and GI complaints. The FDA did issue a box warning because veltassa can bind other drugs thus potentially reducing their absorption. Therefore, it will be crucial to take apart from other medications. Cost remains another hurdle before its widespread use. Lastly, how will the use of these agents affect long term outcomes? Will keeping diabetic patients on their RAAS blockade result in improved outcomes or are me just merely treating a number? Hopefully, we will find theses answers in years to come. For now, at least we are starting to see some research into an area that has long been neglected. Hey, we even saw a trial using kayexalate this year. Go figure.

2. The SGLT2 inhibitor empagliflozin results in improved kidney outcomes presented at ASN Kidney Week 2015 (38%)- Probably the biggest surprise of the year was the kidney (and cardiovascular) outcome data with the SGLT2 inhibitor empagliflozin in patients with diabetes. The cardiovascular outcome data was reported in NEJM earlier this year and they are equally impressive. The EMPA-REG trial was a randomized controlled trial in patients with type 2 diabetes with high cardiovascular risk. The trial consisted of 2 doses of the SGLT2 inhibitor empagliflozin on background of standard care compared standard care alone. ~7000 patients were randomized to the 3 groups. The primary outcome of death from CV cause, nonfatal MI or nonfatal stroke occurs in 10.5% of the empagliflozin group compared to 12.1% in the standard arm. This was mainly driven by death. At ASN the group presented the kidney outcome data (results still not published). These are nicely summarized on UKidney (with figures!). These data are remarkable. At 4 years out both of the empagliflozin groups had preserved eGFR while the placebo group had a fall in eGFR. The data started to diverge by week 94. An interesting point is that the eGFR curves look remarkable similar to ACEi or ARBs in DM with reductions in albuminura to boot. The only major AE was genital infections. I hope we are able to vet all of the data soon. Future NephJC? We also have the CREDENCE study to look forward to which will examine renal outcome with canagliflozin in patients with CKD and DM. Take a look at @neph_spriros storify of the late-breaking clinical trials for even more info.

1. SPRINT Trial presented at AHA and reported in NEJM (65%)- Coming in at number 1 is the SPRINT Trial. This was the most talked about story of the year hands down. 2015 was all about SPRINT. From the premature halting of the trial, to the controversial NIH press release lauding the outcome in the low BP group (before the data was even released), to the eventual presentation at AHA and publication in NEJM. This is all nicely broken down by Swapnil over at NephJC. The study consisted of ~9000 patients (none with DM) who were randomized to either the low BP arm with goal of 120 systolic or the usual care arm of 140 systolic. The SPRINT trial was ongoing when the controversial JNC8 guidelines (the '14 NephMadness champion) were dropped in Dec of 2013. JNC8 was clouded by the failure of intensive BP control (goal 120 systolic) to improve outcomes in patients with diabetes in the ACCORD trial. JNC8 recommend to relax BP goals in certain populations and so the positive result that we saw in the 120 target arm in SPRINT will really tear the JNC8 guidelines apart. The main outcome differences between the two arms were lower rates of fatal and nonfatal major cardiovascular events and deaths from any cause. However, the lower BP group did have more adverse events. Most notably AKI. One of the other interesting aspects of SPRINT is how aggressive they were at controlled BP at frequent visits with multiple BP checks at each visit. Many are already considering this approach in their clinic. SPRINT is a landmark trial that will impact clinical care. Let's hope that we take an individual approach when targeting a BP of 120. This will result in more meds, more side effects, and more AEs. If applied appropriately, SPRINT has the potential to impact patient care.

Another busy and exciting year in the world of nephrology in 2015. Thanks to all of the contributors and readers in the nephrology online community for keeping nephrology fun, interesting and educational.

Thanks for supporting RFN and happy holidays. Can't wait to see what 2016 has in store!

Don't forget to sign up for the NephJC email to keep up to date

Top nephrology-related stories of 2014

Another year has come and gone. 2014 featured some novel therapies for hyperkalemia and the notable failure of the SYMPLICITY-3 trial for renal denervation in resistant hypertension. ASN Kidney Week continues to grow and each year includes more and more social media. Its fun to be a part of it.

I also want to make a last minute honorable mention:

The new US Kidney Allocation System- This had been in the works for several years and was implemented on December 4th of this year. Some of the highlights of the new system are; 1. credit is given for time on dialysis prior to listing 2. patients with blood type B will be able to receive a blood type A2 kidney and highly sensitized patients will receive points to allow for more of a change for transplant. 3. an attempt to match kidneys based on "longevitiy". 4. increased sharing across the country. These changes are supposed to level the field so kidney transplants are allocated equitably across socioeconomic lines. It also attempts to find ways to offer more kidneys to patients that are highly sensitized while pair a kidney with the right donor. How this plays out across the US will be the true test.

Below are links to the last 4 years of the top nephrology stories polls

2010
2011
2012
2013

And now for the top 10 of 2014 and the 5th straight year of top nephrology stories on RFN...

10. POSEIDON Trial showing fluid administration guided by LV end diastolic pressure reduced contrast-induced AKI (6%)- Coming in at number 10 this year was an interesting study reported in the Lancet. This was also covered during NephJC journal club as well. POSEIDON was a single center study with ~400 patients with high risk for contrast-induced AKI undergoing coronary angiography. Patients were randomized to either control (0.9% NS 1hr before and 4hr after cardiac cath) or the intervention arm (the same 1hr pre NS dose but gave NS post cath based on LVEDP). The strategy was to maximize fluid administration while minimizing volume overload in order to prevent AKI. The patients in the intervention ended up getting more fluids and thus a reduction in AKI from ~16% to ~7%. How can these results be translated to other settings (such as CT scan with contrast)? Measures of LVEDP are more difficult to obtain when you are not performing a heart cath. My take away from this study is that patients at high risk for AKI need significant volume expansion and the more you can safely give the better. Strategies to minimize fluid overload will be needed to mitigate the risk of volume overload .

9. Gestational HTN or preeclampsia was more common in kidney donors (6%)- This was an interesting study reported in the NEJM in November. This group utilized a retrospective cohort of 85 healthy women in Ontario, Canada who underwent kidney donation who later became pregnant. These women were compared in a 1:6 ratio with 510 healthy non-donors in the general population who became pregnant. They reported that gestational hypertension or preeclampsia were more common in the donor population compared to healthy controls (11% versus 5%). This finding comes on the heals of several reports linking kidney donation to small by statistically significant increase in ESRD. Paul has a nice review on RFN. The caveat to each of these studies is that they are retrospective case-control studies. While kidney donation might confer some risk, the benefit conferred to the recipient in terms of quantity and quality of life are substantial.

8. Patiromer OPAL-HK trial for hyperkalemia (7%)- It is likely that patiromer and ZS-9 will be in a death match for potassium binding supremacy. The OPAL-HK trial (reported in NEJM) studied 243 patients with mild (av 5.3 mmol/l) and moderate-to-severe (av 5.7 mmol/l) hyperkalemia to treatment with patiromer (a nonabsorbed polymer that binds potassium in exchange for calcium). The study showed remarkable efficacy in lowering potassium in both groups. During the randomized withdrawal phase the majority of patients assigned to placebo had recurrent hyperkalemia. Safety signals include mild to moderate constipation. It will be interesting to see how this drug will stack up against ZS-9. Having 2 drugs in the fight could equal a win in the pricing war. We will see.

7. IgA Nephropathy GWAS implicates genes involved in helminth immune response (7%)- This was the surprise of the year in my opinion. This was a genome wide association study (GWAS) in IgA Nephrology and was reported in Nature Genetics. This group performed GWAS on ~2,700 patients with biopsy proven IgA Nephropathy and ~3,900 controls of European and Chinese ancestry. They found 6 new associations, 4 in ITGAM-ITGAX, VAV3 and CARD9 and 2 new independent signals at HLA-DQB1 and DEFA. "Most loci were either directly associated with risk of inflammatory bowel disease or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The risk alleles were highly suggestive of helminth diversity adaptation". So it appears that yet another kidney disease could be linked to infectious pathogens (see APOL1 and Trypanosoma brucei rhodesiense).

6. HALT-PKD Trials of low BP target and ACEi/ARB combo (10%)-  The much awaited dual release of the HALT-PKD trials were presented and simultaneously reported in NEJM at kidney week this year. HALT-PKD consisted of 2 trials: the first study was termed "early" in which patients had preserved renal function and the other termed "late" in which patients had a decline in renal function. They both tested dual ACEi/ARB blockade and the "early" study had an additional focus on blood pressure reduction. 120/70 to 130/80mmHg (Standard BP) and the low blood-pressure target group was quite low at 95/60 to 110/75 mm Hg (Low BP). Both the "early" and "late" trial dual ACEi/ARB combo groups had no additional benefit over monotherapy. However the "low BP" arm of the "early" study had benefits in LVH, kidney size and urinary albumin excretion at the expense of dizziness and light-headedness. However, this did not confer eGFR benefit. How these results would translate into clinical benefit is uncertain. It is clear that combo ACEi/ARB therapy is done in this patient population as it is for diabetic kidney disease (see Nephron-D). Will it be feasible to push blood pressure this low in patients with PKD. Without changes in eGFR or another solid end-point my guess is no.

5. Anti-Phospholipase A2 receptor assay licensed for commercial testing (13%)- Another exciting development in the field was the news that the anti-phospholipase A2 receptor assay gained clearance for commercial use by the FDA. This test has the potential to really help guide therapy in patients with membranous nephropathy. A recent paper in CJASN and covered in CJASNeJC discusses the potential application of this assay in membranous. Much is still to be learned about how the measurement of anti-PLA2R will affect treatment but this could be a much needed non invasive insight into the disease process. 2015 will surely be filled with more research into the topic. Some questions that remain to be answered. 1. Would you re-initiate immunosuppression if titers increase in absence of worsening proteinuria or worsening renal function in a patient with biopsy proven membranous? 2. Could this test bypass invasive biopsy in select patients? 3. How often should you measure titers? 4. Could anti-PLAR2 offer another index to gauge prognosis and potentially lengthen or intensify therapy?

4. ZS-9 trials for hyperkalemia (14%)-  Coming in a number 4 is ZS-9. Another "potassium buster" drug for hyperkalemia. The company ZS Pharma reported the results of 2 trials, the HARMONIZE trial in JAMA and a phase 3 trial in NEJM. Both these studies showed efficient potassium lowering versus placebo and rebound once the drug is discontinued. NephJC hosted a lively twitter discussion about the HARMONIZE trial. Concerns for how ZS-9 will be tolerated long term and why it was compared to placebo and not kayexalate or diet. Also, in the high dose group more patients had peripheral edema. ZS-9 has the potential to really change the landscape of hyperkalemia treatment, but long term safety data is needed. The other positive from all of the hyperkalemia trials is that the medical community is finally actually starting to study this.

3. SYMPLICITY-3 trial for renal denervation in resistant HTN (19%)-  Probably the biggest disappointment of the year was the SYMPLICITY-3 trial. An introduction isn't even needed as the results have been widely publicized and critiqued. You can read a summary from NOD Kidney Konnection. The SYMPLICITY-3 trial was performed in response to the FDA who requested a sham procedure group be used as a control against renal denervation in patients with resistant hypertension. The results have reverberated across the medical community. Both the sham and denervation groups had impressive drops in blood pressure by ~15 mm Hg. This was the problem. What went wrong? Was it ineffective denervation? Was it a powerful placebo effect? Was it the Hawthorne effect? Bottom line is this trial didn't achieve a significant benefit in renal denervation. Questions remain as to the effectiveness of the actual denervation technique. Will industry put money back into this technology after the results of SYMPLICITY-3? We will see.

2. JNC8 Hypertension Guidelines published in JAMA (22%)- Coming in at number 2 and the winner of NephMadness 2014 is JNC-8. This was an honorable mention in 2013 as it was published online after the end of the year poll. These guidelines were much anticipated and sometimes referred to has JNC-late. JNC-8 attempted to answer questions using randomized controlled data while carefully adjudicating the available evidence. JNC-8 is far narrower in scope than JNC-7 and was not a “how to” document. JNC-8 explicitly states places where we do not have evidence for and what we really need to know. Lastly, the document simplifies the blood pressure goals. Some have expressed concern about raising the systolic blood pressure target in patients over 60 (without DM or CKD) from 140 to 150 mm Hg. For a review of the major changes with JNC-8 see the NephMadness champion post.

1. Perivascular Gli1+ progenitors contribute to myofibroblast pool leading to fibrosis in multiple organs including kidney (57%)- Coming in at number 1 this year is an interesting report from Cell Stem Cell. I'll have to add an asterix to this win though. It appears the stem cell community really got the word out to vote for this one. It is still deserving of a top story of the year as it paves a new paradigm in the pathogenesis of fibrosis. In a real tour de force Kramann et al not only define this process in kidney fibrosis but also look at lung, liver and heart fibrosis. They utilized lineage tracing to show that tissue-resident (not circulating) Gli1+ cells (pericytes) proliferate after kidney, lung, liver, or heart injury to generate myofibroblasts. This has been a hot topic and covered in detail in this years NephMadness. Next, they genetically ablated these cells and induced organ injury in various mouse models. They showed that kidney and heart fibrosis was substantially less compared to controls. These are exciting studies that have the potential to open new therapeutic targets for chronic kidney disease and other chronic disease such as cirrhosis, lung fibrosis and heart failure. This could be a candidate for the next basic science NephJC discussion. An exciting development and it will be fun to watch where this goes.

Another busy and exciting year in the world of nephrology in 2014. Thanks to all of the contributors and readers for keeping the site fun, interesting and educational.

Thanks for supporting RFN and happy holidays. Can't wait to see what 2015 has in store!

Top nephrology-related stories of 2013

The votes are in! Hard to believe that another year has come and gone. RFN has presented the top 10 stories as voted by the readers of RFN since 2010. 2013 proved to be another interesting year. This years list is almost completely dominated by clinical trials. Basic science was snubbed this year (unlike other years). New this year was the active participation of the nephrology blogosphere in promoting different stories. Eleven different people posting on six different blogs and discussed why some of the stories were worthy of the top 10 list this year. These bloggers included Joel, Christos and Ed El Sayed over at PBFluids. Myself and Edgar at eAJKD. Adrian at Red Beans. Kenar at Nephron Power. Pascale at WhizBANG. Andrew, Paul and Gearoid here on RFN. This was a lot of fun and a great learning opportunity. Going into greater detail and hearing about different perspectives about how each of these stories might impact the field of nephrology was nice. This year set a record in voting at 155. Thanks to all who took the time to vote. As always this is not by any means a comprehensive list. If you have additions, feel free to add your story below as a comment. Now lets get to it...

First, a review of the top stories for the last several years can be found below.
Top stories of 2010
Top stories of 2011
Top stories of 2012

Hold up, stop the press, we have a last minute addition..
Honorable Mention- The much awaited hypertension guidelines (JNC 8 aka JNC late) was finally published in JAMA. I guess it is fitting that JNC 8 was published AFTER the year-end poll. The recommendations were a vast simplification to the JNC 7 report. In a nutshell, the JNC 8 committee recommended to treat blood pressure to 150/90 (JNC 7- 140/90) in patients greater than 60 yrs old and 140/90 (JNC 7- 130/80) for everyone else including patients with CKD, diabetes and those less than 60 years old. The new guidelines also recommend black patients take either a thiazide diuretic or a calcium channel blocker (CCB) as initial Rx. They recommended non-black patients to take thiazides, ACEi, ARB or CCB. Patients with CKD should be on ACEi or ARB. JNC 8 will still be fair game for next years top nephrology-related story.

10. Controversial cholesterol guideline published by AHA/ACC (14%)- Coming in at number 10 is the new cholesterol guidelines published in JACC by the AHA/ACC. There was much debate about the calculator that accompanied these guidelines as many felt that it was flawed and over-estimated the risk of cardiovascular disease. This over-estimation (75-150%) would place many more people on statins that would not be warranted. Joel over at PBFluids has a nice discussion about this. For a review on treating cholesterol in patients with kidney disease check out Andrew's post at RFN.

9. A novel potassium binder ZS-9 presented at ASN (14%)- This was a big surprise for just about everyone at ASN this year. However, the study is not published yet. The medical community is sorely in need of a better potassium binder for treating hyperkalemia. This is a frequently encountered problem with life threatening implications. Sodium polystyrene sulphonate (kayexalate) has been put through the ringer as of late. Many have been calling into question its effectiveness and potential risks (bowel necrosis). For another view on SPS check out Joel at PBFluids. The company ZS Pharma presented results from a phase II clinical trial and demonstrated that ZS-9 was capable of lowering potassium with minimal side effects. This could be a huge breakthrough and a much needed drug to treat a common medical condition. This is a well-deserved top story of the year in my opinion.

8. APOL1 risk alleles linked to CKD progression in AASK and CRIC cohorts presented at ASN and published in NEJM (15%)- The story of APOL1 risk alleles continues to gain traction in the medical literature. This year at ASN the story deepened with a study by Parsa et al. I discussed this on eAJKD. The authors showed that having 2 APOL1 risk alleles was associated with faster decline of kidney function in both the AASK and CRIC cohorts. The original APOL1 study published in Science was the #4 RFN top story of 2010. This is an exciting avenue of investigation as a target for APOL1 could have huge ramifications in treating kidney disease. However, this could be a long way off.

7. JASN paper by DeSilva et al showing that Fistula First perhaps not best for Elderly CKD patients (16%)- Coming in at number 7 is a very interesting paper from DeSilva et al in JASN. The Fistula First campaign has largely been seen as effective in decreasing the number of patients initiating dialysis with either a catheter or a graft. However, the benefit of performing dialysis with a fistula over a graft might not be apparent until several years. Is is possible that the survival benefit of a fistula over a graft is lost in the elderly? This group showed that in patients over 80 years old mortality did not differ between patients with a fistula versus a graft. Furthermore, they show that patients receiving a fistula were much more likely to require a catheter at some point as compared to a graft. An accompanied editorial states that we should shift our focus from a "fistula first" to a "patient first" approach. A one size fits all approach to medicine can be dangerous. This is an important study and worthy of the top 10 list.

6. Tolvaptan fails to gain approval from FDA for ADPKD (18%)- Number 6 is #TeamTolvaptan. Joel pushed for this story to be the number one story of the year over at PBFluids. Patients with CKD and in particular ADPKD have few pharmacological weapons to combat the relentless decline of renal function. The results of the TEMPO3:4 trial was the number 1 story of last year and the nephrology community was hopeful tolvaptan would gain FDA approval for ADPKD this year.  However, this was not the case as the FDA focused on liver toxicity and lack of hard outcomes (no ESRD outcomes only change in cyst size and slope of creatinine). I hope we see the tolvaptan story making the number 1 story of 2014 with approval from the FDA. We will see.

5. Abatacept in B7-1 Postivie Proteinuric Kidney Disease presented at ASN and published in NEJM (22%)- This was a small case series published in NEJM of abatacept (fusion protein composed of the Fc region of IgG1 fused to CTLA-4 inhibiting B7-1 binding) in patients with FSGS. Five patients with FSGS underwent immunostaining for B7-1 and showed positivity. These patients were subsequently treated with abatacept. All had either a partial or a complete remission. The thought is that B7-1 activation leads to podocyte dysfunction and abnormal motility through its interaction with beta-1-integrin. Paul discussed the utility of abatacept in FSGS, Lupus Nephritis and Diabetic Nephropathy on RFN. I hope a large trial will be underway soon as these are encouraging results.

4. RAVE Trial showing Rituximab as effective as conventional immunosuppression as induction agent in ANCA vasculitis reported in NEJM (25%)- The use of rituximab has continued to gain popularity treating a variety of autoimmune-related diseases. The difficulty in treating ANCA vasculitis is that the toxicity of the meds can sometimes be worse than the disease itself. Enter the RAVE trial. This was a randomized trial originally published in 2010 and demonstrated non-inferiority of rituximab as compared to oral cyclophosphamide for remission of severe ANCA associated vasculitis at 6 months. The follow-up to RAVE was reported in NEJM and discussed by Paul at RFN in December. In the RAVE trial the experimental group received rituximab and those who had remission only recieve placebo therafter. Whereas the comparison group received continued immunosuppression with cyclophosphamide followed by azathioprine (conventional group). Overall results showed that the rituximab group was non-inferior to the conventional group at 18 months. Rituximab was also superior to conventional immunosuppression in relapsing patients over the first 12 months. Interestingly and surprisingly, adverse events were similar between the two groups. These are encouraging results and adds to the armamentarium of drugs for ANCA vasculitis.

3. JASN paper by Maduell et al showing Online Hemodiafiltration reduces mortality compared to standard HD (27%)- Online hemodiafiltration continues to gain traction in Europe but its use the US has been slow to catch up. Online hemodiafiltration is a technique that involves the addition of convective clearance (hemofiltration) to the diffusive clearance of hemodialysis. This gives better middle molecule clearance of uremic toxins. Maduell et al reported in JASN this year a multicenter, open-label, randomized controlled trial with 906 patients on HD with either hemodialysis versus online-hemodiafiltration. After 2-years the online hemodiafiltration group had a 30% reduction in mortality (P=0.01). Paul at RFN reviews the evidence for why online hemodiafltration has gained momentum in Europe. Lets hope the big dialysis groups catch on and start offering this therapy to patients on hemodialysis. 

2. NEPHRON-D trial presented at ASN and published in NEJM (27%)- Number 2 is the NEPHRON-D trial. Edgar covered this at eAJKD and Ed Al Sayed at PBFluids. This trial effectively put the nail in the coffin of combined ACEi/ARB therapy for diabetic nephropathy. In short the trial was stopped early due to adverse events such as  hyperkalemia and acute renal failure, but still didn't show a difference in CKD progression or death. Even though this was a negative trial it answered an important question about the use of combination therapy and appears that readers agree as it is the number 2 story of the year.

1. CORAL trial for Renal Artery Stenosis presented at AHA and published in NEJM (33%)- Coming in at number 1 is the CORAL trial. This was presented at AHA Scientific Sessions and published in NEJM. As with combo ACEi/ARB therapy this is another nail in the coffin for this time stenting renal arteries in hypertension associated with renal artery stenosis. The CORAL trial was a large trial of 947 patients with renal artery stenosis. There was no difference in any of the outcomes most notably death, MI, stroke, progression of CKD or need for RRT. Jonathan has a nice discussion about this trial at RFN. There still could be a small subset of patients who might benefit from stenting (e.g. flash pulm edema). However, this could be the end of routine stenting in renal artery stenosis.

Again, quite a busy and exciting year in the world of nephrology in 2013. Thanks to all of the contributors and readers for keeping the site fun, interesting and educational.

Thanks for supporting RFN and happy holidays. Can't wait to see what 2014 has in store!

Top nephrology-related stories of 2012

It's hard to believe another year has come and gone. 2012 proved to be a year of ups and downs in the nephrology community. Large clinical trials from the failed phase 3 bardoxalone study in diabetic nephopathy to the positive results of the tolvapan TEMPO 3/4 trial in ADPKD dominated the scene. The passing of a transplantation pioneer and Nobel Prize awardee Dr. Joseph Murry and the awarding of the 2012 Nobel prize to Drs. Lefkowitz and Kobilka for their work on G-coupled protein receptors were two stories that also garnered attention. This is by no means a complete list of all of the major news stories this year. Feel free to add to the list in the comment section below. As usual, I will summarize each of the top 10 studies/stories that you voted for in our year-end poll in increasing order of votes (in %). A total of 78 votes were received. 

10. PEAK data showed that first-year mortality on dialysis was cut by 12% (14%)- Kidney Care Partners launched the Performance Excellence and Accountability in Kidney Care (PEAK) effort in 2009 in an attempt to decrease the high mortality (2009 USRDS data showed a 30% first year mortality) that is seen in patients during the first year of dialysis. The goal was to decrease first year mortality by 20%. This campaign focused on patient education, case management, nutrition, anemia management, dialysis adequacy, catheter use and psychological and social support. The results showed a cumulative 12.5% drop in first-year mortality after dialysis initiation. The data was presented to a congressional educational briefing to help maintain adequate funding of ESRD care. These results are encouraging and with more concerted efforts I hope the goal of further reduction is reached. 

9. Drs. Lefkowitz and Kobilka awarded the Nobel Prize in Chemistry (15%)- Dr. Lefkowitz and his former post-doc Dr. Kobilka both received the Nobel prize in chemistry in 2012 for their body of work on G protein-coupled receptors. This important work defined how cell surface receptors mediate some of the basic physiological functions mediating both normal homeostasis and pathologic disease. The majority of medications used to treat hypertension, kidney disease and cardiovascular disease target G protein-coupled receptors. These include alpha- and beta- adrenergic receptor blockers and angiotensin receptor blockers (ARBs). This was quite an achievement that has led to the development of a large repertoire of medications to treat not only cardiovascular disease but many other diseases such as depression (SSRIs), allergies (anti-histamines), and many others.  Congrats to a well deserved award. These groups are further defining how these receptors signal. An phase II clinical trial exploring the novel beta-arrestin biased angiotensin receptor ligand in heart failure is ongoing.  

7. Chloride restrictive IV fluid administration shown to be superior to chloride liberal in the ICU published in JAMA (21%)- This was a provocative study performed in an ICU setting at a single center at the University of Melbourne, Australia. Joel Topf at PBF and Gearoid here on RFN have excellent blog posts about study and its implications. In short these investigators conducted a prospective, open label, sequential period study in 760 ICU patients comparing a control group with usual practices (chloride liberal) to an experimental group that instead received lactated solution (Hartmann solution), Plasma-Lyte 148 or chloride-poor 20% albumin (chloride restrictive). The primary outcome was looking at an increase in baseline creatinine to peak creatinine and AKI as dictated by RIFLE criteria. They reported that the chloride restrictive group had a lower change in creatinine (0.16) vs. chloride liberal group (0.25). Interestingly they found a significant reduction in AKI with a much lower need for acute dialysis (78 in the liberal vs. 49 in the restrictive).  However, no differences were seen in mortality or length of ICU stay. As Joel stated in his PBF post "this is an intriguing paper and I look forward to more data, even if it means the surgeons were right". 

7. Passing of Dr. Joseph Murray first surgeon to successfully perform a kidney transplant (21%)- Coming in at a tie for 7 in our poll is the passing of a giant in field of nephrology- Dr. Joseph Murray at age 93. Ajay Singh at The Kidney Doctor has an excellent post about Dr. Murray. In 1954 he performed the first successful kidney transplant at the Peter Bent Brigham Hospital in Boston, MA between the identical Herrick twins. This was truly a monumental achievement that ushered in a new era in the treatment of kidney failure. I would recommend reading Surgery of the Soul, a autobiography of Joseph Murray.

6. Diuretics beat ultrafiltration in decompensated CHF published in NEJM (29%)- Coming in at number 6 pitted aggressive therapy with diuretics and vasodilators (pharm group) in 94 patients versus mechanical ultrafiltration (UF group) in 94 patients with decompenstated heart failure (the CARRESS-HF trial). This trial was stopped early due to a lack of evidence of benefit as well as an excess of adverse events with ultrafitration. Before this trial was published the use of mechanical ultrafiltration was starting to garner more popularity as a means of volume removal in CHF with cardiorenal syndrome. However, this study reported that the use of stepped pharmacologic-therapy (diuretics and vasoactive agents) was superior to ultrafiltration. The pharmacologic group had a -0.04 increase in creatinine while the UF group had a +0.23 increase at 96 hrs. There was no difference in weight loss between the groups.  However, there was more serious adverse events in the UF arm (72% vs. 57%) owing mainly to bleeding, renal failure (17 UF and 14 Pharm) and catheter complications. There was no difference in mortality (although there was a trend towards higher mortality in the UF group) or rehospitalization rate. This trial puts serious question to the use of UF in decompensated CHF with cardiorenal syndrome. Read the editorial accompanying this article for more perspective.

4. Results of ALTITUDE trial using aliskiren combined with ACEi and ARB published in NEJM (30%)- Coming in at at tie for 4th was the ALTITUDE trial. The results were presented at ASN Kidney Week in San Diego this year and published simultaneously in the NEJM. This was a large prospective double blinded placebo controlled trial involving 838 centers in 36 countries. 8606 patients with type 2 diabetes were randomly assigned to 2 groups- Placebo  + ARB or ACEi or Aliskiren (300mg) + ARB or ACEi. This trial was stopped early after the planned second interim efficacy analysis where they concluded that the increased rate of adverse events was not offset by any measurable cardiovascular or renal benefit from aliskiren and in fact favored the placebo arm. The primary end-point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resus, nonfatal MI, nonfatal stroke, heart failure hospitalization, ESRD, death from renal failure, doubling of serum creatinine. The primary end point was reached in 783 patients in the aliskiren arm and 732 in the placebo arm. (P=0.12 CI 0.98 to 1.20). BP was lower in the aliskiren group as was the amount of albuminuria. However, there were no differences in secondary renal end point. There was an increase in adverse events in the aliskiren arm most notably hyperkalemia and hypotension. This was a large well conducted trial that does not the support the addition of direct renin blockade to ACEi or ARB therapy in patients with type 2 diabetes and chronic kidney disease.

4. Supreme Court upholding of the Affordable Care Act (30%)- The Supreme Court determined that the Affordable Care Act (ACA) was constitutional with the exception of the mandatory medicaid expansion earlier this year. Dr. Barry Staube, former Chief Medical Officer of CMS and current Director of the Marwood Group discussed how the ACA will affect patients with kidney disease and their providers in a brief commentary at eAJKD.

3.  Results from the EVOLVE trial using cinacalcet in ESRD published in NEJM (33%)- Coming in at number 3 is the behemoth EVOLVE trial also presented at ASN Kidney Week in San Diego this year and published in NEJM. This was the largest and longest randomized clinical trial ever performed in patients on dialysis. Joel Topf reported on this story at eAJKD and in more detail at PBF. The trial was designed to test the hypothesis that treatment with cinacalet (an allosteric modifier of the calcium sensing receptor, a G protein-coupled receptor) would reduce the risks of death and nonfatal cardiovascular events among patients with secondary hyperparathyriodism who were undergoing dialysis. They found that the main cardiovascular end-point was not significantly different from the placebo arm nor was all cause mortality. However, as pointed out by Joel and discussed in the NEJM article, the cinacalcet group was on average older (55 yrs vs. 54) and age-adjusted analysis did show a "nominally" significant reduction in mortality. A significant reduction in parathyroidectomy was also noted. Side effects were seen in both groups but were more frequent with cinacalcet (hypocalcemia, nausea and vomiting). How this study will change practice will be born out in time. I applaud all of the investigators in pursuing an important issue that is germane to both patients and providers.

2.  Phase 3 clinical trial (BEACON) testing bardoxolone in diabetic nephropathy abruptly stopped (38%)- The biggest shock of the year comes in at number 2. Just a few weeks before ASN Kidney Week came the announcement from Reata that the BEACON trial was stopped. They cited "excess serious adverse events and mortality in patients taking bardoxolone". RFN first picked up the story back in 2010 when I posted on preliminary results from the first 24 weeks of the 52 week phase IIb study that was presented at ASN that year. At that time it was noted that patients in the bardoxolone group had a mean elevation in eGFR of 10 ml/min when compared with the placebo arm. This was odd given that our most successful therapies, ACE inhibitors and ARBs typically lead to a drop in glomerular pressure and a slight rise in creatinine when started. In addition it was also noted that there were higher rates of nausea, decreased appetite, hypomagnesemia and muscle spasms with bardoxolone. The full results of the 52 week study were eventually published in NEJM and commented on by Gearoid. Again the rise in eGFR and higher adverse event rates were noted with bardoxolone but now additionally a rise in albuminuria was seen. Some interesting potential mechanisms for this emerged, including a down regulation in megalin which Gearoid posted on and the idea that albuminuria is not a perfect surrogate for future changes in renal function was also raised and commented on at PBF.  With the above as backdrop, bardoxolone was the RFN number 5 story of the year in 2011.  When the phase 3 study folded, Reata bailed on Kidney Week, no attempt to impart lessons learned or what next steps for the scientific community might be, just disappeared. Bardoxolone received a lot of hype and there was hope that this drug would represent a significant new treatment for patients with diabetic nephropathy. Looks like the end of the road for bardoxolone.

1. Results from TEMPO 3:4 trial using tovaptan in ADPKD published in NEJM (51%)- The major bright spot of the year was at ASN Kidney Week in San Diego to a packed late-breaking clinical trial audience when the TEMPO 3:4 results were presented. This was also reported by Joel at eAJKD. This was a randomized double blinded placebo controlled clinical trial comparing the vasopression antagonist tolvaptan to placebo in patients with Autosomal Dominant Polycystic Kidney Disease.  This study showed  that tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD. This is a major breakthrough, but several questions remain.  How will these results this hold up over time and will this drug decrease the rate of progression to ESRD. Furthermore, the cost of tolvaptan is considerable and this therapy would be lifelong if proven effective.

Again, quite a busy and exciting year in the world of nephrology in 2012. Thanks to all of the contributors and readers for keeping the site fun, interesting and educational.

Thanks for supporting RFN and happy holidays.

Top nephrology-related stories of 2011

 

2011 proved to be another exciting year in the world of nephrology.  2010 was dominated with big clinical trials (SHARP, FHN, IDEAL), APOL1 gene variants, Propublica article on HD in the US, and medicare bundling.  2011 proved to be a big year in basic science.  Below is a list of the top 10 nephrology-related stories as voted by the readers of RFN. This is by no means a complete list of all of the major news stories.  Feel free to add to this list in the comment section below.  I will summarize each of these studies/stories below in increasing order of votes as received in our year-end poll.

10. FDA approval of belatacept for use in kidney transplant induction therapy (15%)-  In June the FDA approved the use of the selective T-cell costimulatory blocker (anti-CTLA-4) belatacept (Nulojix) for use in kidney transplantation as both induction and maintenance therapy.  This was after the FDA reviewed both the BENEFIT and BENEFIT-EXT trials published in Transplantation in 2010. These trials examined the use of belatacept for induction therapy and as a replacement for calcineurin-inhibitors for maintenance therapy. The hope is that calcineurin-inhibitor based regimens can potentially be avoided in the future as these are associated with a decline in eGFR over time. These trials both showed an improvement in eGFR at 3 years as compared to cyclosporine based regimens with slightly more acute rejection. However, the major concern for belatacept is the increased risk of post transplant lymphoproliferative disease hence it cannot be given to EBV negative patients. Another issue with giving belatacept is that it is given IV at different schedules after transplant which could impart challenges.  Nephron Power has a post about this story.  

9. Success in treating myeloma kidney with bortezomib plus plasma exchange published in NEJM June (17%)- Using plasma exchange to treat myeloma cast nephropathy has been a controversial topic in the field of nephrology. The benefit in clearing free serum light chains with plasma exchange has become an increasingly popular approach. Investigators from the Mayo Clinic published a letter in NEJM in June of this year describing their experiences with using bortezomib in combination with plasma exchange in 14 patients with known or suspected myeloma cast nephropathy.  12 of the 14 patients (86%) treated with plasma exchange had a partial or complete response to the therapy.  6 of the 12 had a complete response with normalization of creatinine after 6 months.  Only 2 were on HD after treatment. These results are encouraging, however a randomized clinical trial will be needed to confirm this.

8. Eculizumab for shiga associated HUS published in NEJM (21%)- The major outbreak of E. coli O104:H4 secondary to contaminated sprouts that occurred in Germany dominated the international news from May to June of this year. About 4000 people were infected and at least 46 died. Nephrologists in Germany were hit with an unprecedented number of patients with hemolytic uremic syndrome (HUS). This coincided with a report published in the NEJM in June of this year which demonstrated the complete resolution of Shiga-toxin-producing E. Coli- HUS in three children treated with eculizumab. This supported the concept that shiga toxin may activate complement directly and direct inhibition of terminal complement complex formation by treating patients with eculizumab. This lead to an ad hoc committee from the German Society of Nephrology to recommend all patients with renal or neurological and hematological symptoms treated with plasmapheresis. If no short-term improvement was seen then they recommended use of eculizumab. This has resulted in wider-spread use and now a clinical trial. This was definitely a positive outcome to a devastating condition.  I'm sure we will see more of this drug in clinical use in the near future.

7. The DOSE study of bolus or drip diuretics in CHF (24%)- This was an interesting study of a common clinical conundrum (Do you give diuretics by bolus or continuous infusion in compensated CHF?) that was published in NEJM in March of this year and discussed on RFN by Finnian. This was a prospective double-blind randomized controlled trial consisting of 308 patients from 26 clinical sites testing 2 questions; how do high-dose (2.5 x home dose) vs. low-dose (home dose) diuretics and IV continuous vs. IV bolus loop diuretic strategies impact the 1.  Efficacy (symptoms) or 2.  Safety (change in creatinine) in patients with compensated heart failure? There were no significant differences between either of these endpoints in either high vs low and continuous vs. bolus diuretic administration. The high-dose group did have more improvement in dyspnea but a higher creatinine level was reached. Read Finnian's conclusion on his blog post.    

6. sFLT-1 removal in preeclampsia published in Circulation in August (25%)-  Another exciting development in nephrology is the publication of a pilot study aimed at removing the soluble fms-like tyrosine kinase 1 (sFlt-1) in women with preeclampsia which was published in the journal Circulation in August of this year. Nate originally discussed sFlt-1 role in preeclampia on RFN and it is interesting to see how far research has progressed since then. This study looked at the feasibility and safety of removing sFlt-1 using extracorporeal apheresis in 5 patients with preterm preeclampsia and elevated sFlt levels. The pilot study confirmed that this technique is possible and safe however, it was not able to address whether or not this approach will prolong pregnancy and improve both maternal and fetal outcomes. I'm sure a clinical trial will be forthcoming.

5. Bardoxolone for diabetic nephropathy published in NEJM July (27%)-  The preliminary results from this trial were originally presented at ASN Kidney Week in 2010 which I discussed on RFN in December. The final results were published in NEJM in July and discussed by Gearoid on RFN and Joel on PBF. This was a phase 2, double-blind, randomized, placebo-controlled trial looking at 227 adults with CKD treated with various doses of the oral antioxidant inflammation modulator Bordoxolone or placebo for 52 weeks.  This trial showed improvement of GFR at 24 and 52 weeks compared to placebo.  However, much of this GFR improvement was lost at 56 weeks (4 weeks after stopping the drug). I think these results are provocative, however I am anxiously awaiting the results of the larger phase III clinical trial termed BEACON which is currently enrolling patients.

4. ACT trial of acetylcysteine in contrast nephropathy (30%)-  This trial published in Circulation in August and discussed by Graham on RFN was another long debated clinical question in nephrology- (how do we prevent kidney injury when patients receive iodinated contrast agents?). This trial randomly assigned 2308 patients undergoing an intravascular angiographic procedure with 1 risk factor for contrast-induced acute kidney injury to either acetylcysteine (1200mg twice daily 1 day before and 1 day after the procedure) or placebo. Both groups received normal saline at a rate of 1ml/kg per hour 6-12 hr before and after. They did not find any difference between any of the primary or secondary outcomes comparing acetylcysteine vs. placebo. Read the conclusion and comments from Graham's RFN post. Overall, it appears that  acetylcysteine's days for preventing contrast nephropathy are almost over.        

3. Increased mortality in dialysis patients after 2-day break (41%)- This study published in NEJM in September examines how patients that receive thrice weekly dialysis fare over the 2-day interdialytic interval. This study retrospectively examined the death rates and cardiovascular related hospital admissions on the long 2-day interval vs. other days in 32,065 patients currently undertaking thrice weekly hemodialysis using the USRDS database. They found that indeed the 2-day interval was associated with increased all-cause mortality, infection-related mortality, cardiac arrest, MI, CHF, stroke and dysrhythmia as compared to other days. Evidence is continuing to point towards a more physiological dialysis regimen with daily dialysis. However, this study did not compare thrice weekly to nocturnal or daily dialysis.

2. The lupus nephritis maintenance phase of the ALMS trial published in NEJM November (44%)-  Coming in at number 2 is the much awaited results of the maintenance arm of the Aspreva Lupus Management Study (ALMS) trial. The induction arm of the ALMS study compared Cyclophosphamide to Mycophenolate (MMF) and was published in JASN in 2009 and showed difference between the two therapies in inducing remission in lupus nephritis. The maintenance phase randomized patients that responded in the initial phase to either MMF or Azathiprine. 227 patients were randomized into each group. The patients randomized to MMF had better outcomes as compared to Azathioprine and puts MMF firmly on the map for both induction and now maintenance of lupus nephritis. However, there has been some conflicting data as was reported by the smaller MAINTAIN study that did not show a difference between these two regimens. This was a well conducted clinical trial that adds evidence to a difficult to treat condition. This is a welcome addition to patients with lupus and the nephrology and rheumatology communities.     

1. suPAR as a cause of FSGS published in Nature Medicine in July (54%)-  Coming in at number 1 in the 2011 nephrology poll at 54% of votes received was a basic science article published in Nature Medicine and discussed by Gearoid on RFN exploring the mechanism of focal segmental glomerulosclerosis (FSGS). This study showed that level of serum soluble suPAR urokinase receptor was present at higher concentrations in patients with FSGS. They then showed in 3 different animal models that elevated suPAR was capable of causing proteinuria and foot process effacement. We will see how these findings will be translated to human studies just as the discovery of the M-type phospholipase A2 receptor is for membranous nephropathy.

Again, quite a busy and exciting year in the world of nephrology in 2011. Thanks to all of the contributors and readers for keeping the site fun, interesting and educational.

Thanks for supporting RFN and happy holidays.