Tag: Uncategorized

Posted on

Top Nephrology Stories of 2013 NEPHRON-D: The End of the Combination Treatment Era

This is a guest post. I don’t think I have ever done this before but we are trying to get as many voices to weigh in on the Top Nephrology Stories of the Year as possible and I knew that I wanted Ed El Sayed (@iApothecary) to be part of this. If you don’t follow him, you should, he is one of the sharpest medical minds on Twitter. When I invited him he said he had no place publish, so I offered a temporary home on PBFluids. Hey Ed, start a Tumblr, they’re free!

Here are his words on the top nephrology story of the year:

Diabetic nephropathy is the leading cause of Chronic Kidney Disease (CKD) and End Stage Renal Disease (ESRD) in the US. It has long been postulated that combination pharmacotherapy with

Angiotensin Converting Enzyme Inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) could slow the progression of nephropathy, and have a positive impact on the prognosis, morbidity, and mortality of patients with diabetic kidney disease. This hypothesis arose from the unfortunate fact that neither ACEi nor ARBs working alone are able to fully block the renin angiotensin aldosterone system (RAAS).

Design of Combination Angiotensin Converting Enzyme Inhibitor Angiotensin Receptor Blocker for Treatment of Diabetic Nephropathy (NEPHRON-D) was a large multi-center, prospective, and parallel trial that was terminated early due to serious side effects. In this study, 1,648 patients (average age of 64 years) with type 2 diabetes, albuminuria, and stage 3 or 4 CKD were recruited. All patients were started on losartan 100 mg and then randomized to receive either Lisinopril 10-40 mg daily or placebo..

As mentioned above, this well designed and well powered trial was terminated early due to a significantly higher rate of adverse events with combination therapy. Investigators reported that the incidence of hyperkalemia was higher with ACEi and ARBs compared to ARBs and placebo (6.3 vs 2.6 events per 100-persons-years with P = 0.001). Acute Kidney Injury (AKI) was also higher with combination therapy (12.2 vs 6.7 events per 100 person-years with P = 0.001).

With 2.2 years of follow up investigators reported no significant difference in the study’s primary end point of progression of renal disease or death (152 vs 132 with P = 0.3).

The ONTARGET and ALTITUDE studies were the two previous attempts to show renal or cardiovascular benefits from combination RAAS blockade (ACEi + ARBs in ONTARGET; ACEi + Renin Inhibitor in ALTITUDE). ONTARGET involved patients with an increased risk for cardiovascular disease but predominantly normal albumin excretion levels, while ALTITUDE involved patients with kidney disease and diabetes who were not necessarily proteinuric. Neither showed any benefit and had increased adverse events with combination therapy.

Experts now have three solid trials that clearly convey one message: Combination pharmacotherapy with ACEi and ARBs in patients with DM induced nephropathy and CKD does not provide any additional benefit and may, in fact, increase the incidence of harm.

It is worthy to note that NEPHRON-D is a perfect example of a “negative” trial that has a huge impact on the strategies used by clinicians in treating their patients; emphasizing the importance of publishing both negative and positive outcome trials.

Update from Twitter:

@kidney_boy IIRC COOPERATE was retracted due to fabricated data, so that only one name should be engraved on that stone
— ChristosArgyropoulos (@ChristosArgyrop) December 11, 2013

Nice discussion about how COOPERATE was retracted via @cardiobrief http://t.co/nEbs4P2cS9
— Matt Sparks (@Nephro_Sparks) December 11, 2013

I set the onset of combo therapy at the publication of COOPERATE because it was a landmark study at the time. It was regularly brought out as justification for the use of dual therapy, because it’s end-point was doubling of serum creatinine or ESRD, not just a change in proteinuria. According to the Cardiobrief pos,t that Dr. Sparks referenced, combo therapy was already in wide use at the time of publication but I think COOPERATE was the study that made its use acceptable to EBM purists.

Posted on

Go #TeamTolvaptan

This is just a picture of the ballot
go to RFN to cast you ballot.

One of my favorite end-of-the-year traditions is Renal Fellow Network’s top nephrology stories of the year. Make sure you vote. The authors did a great job selecting 2013’s top stories of nephrology somehow they forgot the Omontys allergic reaction, voluntary recall and abandonment of peginesatide.

(I thought of one more but it escapes me, I’ll update this post when I remember it.)

Looking over the list, I think the story of the year is Tolvaptan’s failure to FDA gain approval for ADPKD. If Tolvaptan gains FDA approval in the next year or two following re-submission this story will quickly be forgotten. But if the future goes the other way, if Otsuka abandons tolvaptan for ADPKD and decides to remain in the limited ghetto of inpatient management of hyponatremia that would be a tragedy.

Part of what gets my blood boiling is the raging hypocrisy that the very same organization that approved:

  • Zemplar (paricalcitol)
  • Hecterol (doxercalciferol)
  • Renagel (sevelamer)
  • Renvela (sevelamer again)
  • Fosrenal (lanthium carbonate)
  • Sensipar (cinacalcet)
(all drugs that have never been shown to help a patient but merely to improve some biochemical target. Hell, even sevelamer and cinacalcet tried and failed to show reduced mortality and they remain on the market) had the gall to deny tolvaptan for ADPKD.

ADPKD slowed cyst growth and slowed the progression of kidney disease. Not just for one year but for three years! It joins ACEi/ARBs and insulin in the pantheon of drugs that can slow the progression of CKD (though bicarbonate and allopurionol are walking toward the door). Denying it was preposterous.

The other part of my rage comes from possibilities of having tolvaptan available as an outpatient option for patients. I certainly want this drug available for ADPKD but turning it from a limited duration in-patient drug to a chronic outpatient therapy will completely remake the cost structure.
The price will remain high but it will no longer be $300/pill. Let us say $1000 per month. The TEMPO trial used 120 mg per day, so a month worth would be 120 pills. That would go a long way if you were interested in using tolvaptan for aquaresis. This drug is effective at increasing urine output by a mechanism totally novel to us. We are being given control over one of the fundamental control levers of the kidney. There are only limited number of these levers:
Look it how useful the drugs are that affect these hormones. The list is full of all-stars. Tolvaptan has already been proven a winner in ADPKD and maybe useful in CHF. Tolvaptan failed a pivotal trial called EVEREST, but the drug did increase diuresis, fluid loss, and the effects were long lasting. Tolvaptan failed one trial on heart failure, but alternative patient selection or dosing regimens could turn this turkey into another critical tool for heart failure. We need to have this drug available to see where it can be useful because today we are primitives.
If the FDA approves it, the fact that it failed its first application will be quickly forgotten, but if Otsuka decides to retreat from this breakthrough and live happily ever after correcting mild asymptomatic hyponatremia nephrology will be a poorer place.
Posted on

Impact factor for blogs

For people unaware of impact factor, it is the AP Top 25 for scientific journals. It provides a score for every journal based on how often scientific articles cite articles published by the journal. The number of citations is divided by the number of articles published so just pushing a lot of crap through in hopes that some of it gets cited does not inflate your score. The top three medical journals are NEJM, Lancet and JAMA in that order. Journal editors spend a lot of time worrying, strategizing and optimizing in order to improve Impact Factor.

I had the privilege of going to the AJKD editors meeting Kidney Week and saw first hand how IF colors a lot of what they do. Editor in chief, Dr. Levey talked about change in IF over the last decade and what happened over the last year. Then he talked about the different sections of the journal. One recurring entry are the narrative reviews. He says that these are rarely cited so increase the denominator of the IF without moving the numerator. Despite the fact that these hurt the IF they publish them anyways because they see it as part of their mission. Not every journal editor’s morals are so straight.

A different scoring system, called the H-index is used to rank authors and scientists.

Brent Thoma at Academic Life in Emergency Medicine has published a ranking system for blogs and online education. This has sparked an active and colorful debate, here and here. In terms of why he did it, and he said (paraphrasing) “A scoring system will come to open access medical education content. I would like it to evolve out of the community rather than have it imposed on the community. So let’s build our own score.”
Brent is an ER doc and all of the blogs he ranked were of interest to ER doctors. However he published his scoring algorithm and I used it to score PBFluids, Renal Fellow Network, Nephron Power, and eAJKD.
  1. PBFluids edged RFN with 3.02, good for 19th place among the 60 blogs he ranked.
  2. Renal Fellow Network came in right below PBF with a 2.94, good enough to tie for 20th on the list.
  3. eAJKD, scores 2.86, good for 21st place.
  4. Nephron Power had 2.18, good for 36th place.
None of those three had any Google+ presence and NephronPower was hurt by the lack of a Facebook page and minimal footprint on Twitter.
You can view my spreadsheet here. Please add your website if you would like. 
  • Alexa is the website rank according to Alexa.com. Mine was 4,589,000. Enter the rank divided by 1,000. This is a measure of traffic.
  • Page Rank is google’s measure of quality by its analysis of incoming links (and likely a bunch more secret ingredients). You can find out a sites page rank here.
  • Twitter is the number of followers of the principle author.
  • Facebook is the number of likes for the blog on its facebook page.
  • Google+ is some metric around this failed social media site.
Here are how the three sites compared:
Everyone had the same page rank of 4 except NephronPower. Alexa traffic was close, but eAJKD had the highest traffic with RFN in second. PBFluids took first based on the strength of my Twitter following.
This is very interesting to me. I have been thinking about ways to measure blog quality as part of a follow-up study from my poster presentation at Kidney Week. I tracked posts/month to measure productivity but I had no way to assess if the posts were any good. The SM-i seems like a reasonable stab at answering this question, at least at the blog/author level.
Some thoughts: purchasing twitter followers and Facebook likes is a thing and a real index should be resistant to that type of gaming. Additionally, Youtube is a very important educational channel, Nephrology on Demand is just killing it by adding educational content to YouTube, and has over 1,500 subscribers. This should be captured in the SM-i.
Posted on

UKidney’s library of high impact articles

Ukidney has just posted a new page on their website. It is a library of high impact nephrology research articles. Other sites have attempted to do this but this one is particularly well done. The lead-in describes it as a growing library of “key high-impact articles.” They are a little vague on the goal here but I hope they keep the list of articles small and tight. The lazy thing to do would be to include every seemingly important paper with little curation. The most value is added by maintaining editorial vigor and declaring a limited set of articles as the most important. I’d even put a number a number on it. Keep it limited to the 50 most important articles in nephrology. I like 50 because that is a number that a motivated fellow could read in a week.
A good decision in generating the list of articles was not adding the classic articles of nephrology. I was hard pressed to find an article older than 15 years. It would be easy to add Bartter and Shwartz’s original description of SIADH or Thurau’s brilliant essay on acute renal success but those are lessons taught in text books. We read the medical literature to find what is new and the contributors at UKidney wisely limited their list to newer data. A second, separate project might be to find the 50 most important studies in nephrology, even if they don’t affect modern nephrology much, but that should not contaminate this mission.
It will take more oversight and real editorial rigor to keep the library manageable, but that is a valuable mission and separates this project from a dropbox folder of every PDF a fellowship has covers in journal club.
One area that could be improved would be the addition of a 2-3 sentence description of why the contributors feel this article deserves a place in the library. Think of it as the plaque next to the picture in Cooperstown. That kind of meta-data can be so important in putting articles in scientific perspective and it would also give the organizers a venue to justify why each article is important.
To paraphrase Alan Kay, UKidney’s article collection is the first one good enough to criticize.
The site is organized by 9 icons showing the different sections.
I am going to go through it section by section and describe what changes I would make. My decisions are only that, my decisions. There is no right or wrong here, I am just giving my angle.
The first section is anemia. This section has four articles, all of them negative trips of epo: Normalization of hematocrit, CHOIR, CREATE and TREAT. These clearly are the most important articles in the fall of ESAs we have witnessed in the past decade, but they are not all equal. Given the relative size of the trials, this list could be limited to the Beserab trial in hemodialysis and TREAT in CKD.
Also the lack of iron could be corrected by inclusion of DRIVE.

Bone and mineral metabolism 

This section reads like a Genzyme (Sorry, I mean Sanofi) reading list. They included the original article on calcium x phos product and two separate articles on binders and coronary calcification. As appealing and intuitive as coronary calcification is, it is an intermediate end-point that is not validated to correlate with patient outcomes. This view on binders seems unbalanced especially given the conspicuous absence of the negative mortality trial of sevelamer (DCOR). Additionally all of the other dimensions of Calcium, phosphorous and PTH are ignored. Where is EVOLVE and Teng’s retrospective trial of dialysis survival with and without active vitamin D therapy. Also where is Wolfe’s FGF-23 and dialysis mortality study? This section needs a lot more attention. Remove the retrospective and old in order to widen the scope of the section.

Diabetes

The Diabetes page is nearly perfect. One quibbles, I would add the long term follow-up of the DCCT trial because that introduced the concept of metabolic memory and changed the original study from one that affected a questionable intermediate endpoint, microalbuminuria, and replaced it with doubling of serum creatinine.

Fluid and Electrolytes

The fluid and electrolyte page, a subject near and dear to my heart (in case you hadn’t noticed), needs work and I mean a lot of work. Right now it has a case report about a disease you will never see, syndrome of inappropriate diuresis, and a collection of review papers. All of the review papers are excellent but it is hard to consider any review article a high impact article. High impact articles for this section to consider include:

The next section is general nephrology and UKidney wisely created sub-sections to break up the 37 articles in this section. They should add a cystic disease section and a CKD section.

Lipids

Nailed it.

Acute Kidney Injury

The AKI section leads off with a couple of review articles. See above. Then it has a review and meta analysis of NGAL. This can’t be high impact because the test is readily available and no one knows what to do with the data anyways. This article seems out of place in this list. The the ATN trial takes it rightful place on the list. Strangely, right after that is a meta-analysis that recommends the high dose that was disproven in the ATN trial. I say flush Panu’s article. Bringing up the rear is a meta-analysis showing that iHD and CVVH can both be used in ARF. Fine.
Things that are missing from the AKI section is the big meta analysis on renal dose dopamine has a place here. I would also include some of the data from CABG that show increased mortality from minimal increases in creatinine. Also the recently completed CORONARY study along with some of the previous work linking AKI to CKD should be included.

AJKD Core curriculum

No complaints. Clever addition.

Critical Care Nephrology

This looks like a retread from AKI. Only one additional article, a Cochrane Review of IHD versus CVVH. They should collapse these two headings into one.

Glomerulonephritis

I must admit I am not as up to date on the literature in this sub-field as I should be. But overall it looks like they have too many articles on MMF for lupus (3 of the 8 articles). They have nothing on membranous or FSGS. This looks like a half-baked section. I will give them a pass as they work on filling the library.

Hemodialysis

The next major section is hemodialysis. There are a lot of articles on AKI in this section. Though we treat AKI with dialysis, I think this section should be left to chronic dialysis and include PD with HD. 
In terms of missing studies. I would add the Aggrenox study on access patency. They should include some of Agarwal’s work on blood pressure in dialysis patients, they should include the IDEAL study, one of the most important dialysis studies in the last decade. Another important study was Tamura’s study on the deterioration of functional status with dialysis.

Hypertension

The hypertension section seems light to me. It is filled with a number of trials of different drugs. It is missing ALLHAT and AASK but more importantly it is missing aspects of hypertension beyond what drug and what blood pressure target. They should include some Symplicity data, and at least one trial on the importance of ambulatory / home blood pressure monitoring. They should include the Cochrane Review of Pharmacotherapy for mild hypertension and the DASH diet RCT.

The Peritoneal dialysis

The Peritoneal dialysis section is tiny. It makes me think that the PD and HD sections should be combined and form a new section called chronic dialysis. Two additionals would be PD for acute renal failure sepsis (don’t do it) and an article on PD First.

Transplantation

I am not as familiar with this literature as I should be and I honestly don’t know what should be on the list. Though I think that the CJASN study on recurrence of primary disease after transplant should be included.

Posted on

All the tweets of #KidneyWk13

@kidney_boy Brilliant summary of Renal Week activity via Twitter. Particularly good way for us non-attendees to keep in touch. @ASNKidney
— Dr Damian Fogarty (@DamianFog) November 18, 2013

There was an incredible amount of twitter activity at ASN Kidney Week 13. I have downloaded the entire transcript and stitched the 9 pages into a single document for your downloading pleasure. It is 478 pages and 68,000 words long.

If that is not long enough for you could check out the hashtag misspelling at #kidneykw13 or the expanded #kidneyweek or in case you didn’t want any confusion with the epic 1913 ASN Kidney Week: #KidneyWk2013.

Posted on

This never would’ve happened if the AHA/AAC had put Andrew Levey in charge of their risk calculator

Two items of note struck me this morning. The first was the fumble with the new cholesterol recommendations. The guidelines have been taking heat largely because they dramatically expand usage of statins in populations with that receive little to no benefit front he drug.

TheNNT is one of my favorite websites for patient discussions.

The last thing the new recommendations needed was a headline in the paper of record showing that their calculator over estimated 10 year cardiac risk by a mere 75 to 150 percent:

This week, after they saw the guidelines and the calculator, Dr. Ridker and Dr. Cook evaluated it using three large studies that involved thousands of people and continued for at least a decade. They knew the subjects’ characteristics at the start — their ages, whether they smoked, their cholesterol levels, their blood pressures. Then they asked how many had heart attacks or strokes in the next 10 years and how many would the risk calculator predict. 

Look what that risk calculator did to that Church!

The answer was that the calculator overpredicted risk by 75 to 150 percent, depending on the population. A man whose risk was 4 percent, for example, might show up as having an 8 percent risk. With a 4 percent risk, he would not warrant treatment — the guidelines that say treatment is advised for those with at least a 7.5 percent risk and that treatment can be considered for those whose risk is 5 percent.

That’s a big miss and I think it threatens to be a big mess if people lose confidence in our cardiology experts and their guidelines.

 It is interesting that this story is just getting legs today. The alarm was raised on the day the guidelines were released. From Medscape:

To heartwire , Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD), who was not part of the writing committee, said he agreed with 90% of the information in the new guidelines. “To put that in perspective, I probably only agree with my wife 85% of the time,” he said. 

Namely, he is a little troubled by the new atherosclerotic risk score. Derived from FHS, ARIC, CARDIA, and CHS, it hasn’t performed all that well when applied to other cohorts, such as the Multiethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, he said. The risk score does not take into account family history of premature cardiovascular disease, triglycerides, waist circumference, body-mass index, lifestyle habits, and smoking history. 

“In my mind, we’re putting a lot of faith in this risk score,” said Blumenthal. “We’re probably going to be treating many more people, especially many more ethnic minorities, who get above this 7.5% threshold.”

In the end, I think we can agree that the cardiologists should leave the equations and formulas to the nephrologists, namely Andrew Levey. Hence the second item of note. Andrew Levey won the prestigious Belding Scribner Award. Levey is best known for creating the MDRD eGFR estimating formula and its successor the CKD-Epi formula.

I have gotten to know him as he is the editor and chief AJKD and spearheaded the creation of eAJKD. During every one of my encounters with him he has been humble, witty and friendly. During his Scibner acceptance speech he revealed that he considers his greatest moment in nephrology to be donating a kidney to his wife.

Levey donated a kidney to his wife. TLA. #kidneywk13
— Joel Topf (@kidney_boy) November 9, 2013

What a mensch.

There is a great interview with Andre Levey at eAJKD today. Take a moment and read it.

Posted on

My Best Kidney Week

Every year that I go to Kidney Week it seems to get better. I had a wonderful time at this years Kidney Week in Atlanta primarily because it was full of new experiences and connections.

One of the highlights was getting the honor of introducing the KDIGO Mobile app. This iPad only app contains all of the KDIGO guidelines and support documents. The Chair of the implementation committee, Yusuke Tsukamoto, described me as KDIGO’s Steve Jobs. I can’t imagine a higher compliment.

Just got my hair cut. Asked for the full Steve Jobs. What do ya think? http://t.co/DT45QxOa
— Joel Topf (@kidney_boy) September 16, 2011

The app is a great way to read the guidelines. We feel these are our first steps and we are excited to push the app forward. You can download it for free from the iPad App Store. Getting a chance to work with the KDIGO folks on this project has literally been one of the highlights of my career.

I aggressively live tweeted every session I attended. This is a huge 180° U-turn for me. See this post from last August where I blast the entire practice. Hobgoblin of little minds and all. Well all that tweeting resulted in me being the largest influencer of Kidney Week 2013.

That will be the only time I will ever be listed ahead of the New England Journal of Medicine.

The middle column is just the number of tweets by different individuals. I would like to call attention to three new tweeters. I maybe wrong, but I believe @rednephron, @ThePeanutKidney and @KatieKwonMD were all tweeting their first KidneyWeek. It is great to see new tweeters, especially ones who are so good at their craft. Welcome to the community.

Impressions is number of tweets times number of followers. Mentions is the number of tweets where an individual is mentioned along with the hashtag #KidneyWk13. To me this is the most important metric, since it indicates tweets that are generating interactions, through retweets and replies.

Pushing the twitter at #kidneywk13 pic.twitter.com/BWNoNKeMdR
— Joel Topf (@kidney_boy) November 6, 2013

The summary statistics show increasing twitter use at the meeting. Here are 2013’s numbers compared to 2011 and 2012:
Tweets and participants are rising.
I showed my poster on the nephrology blogosphere:

And I was invited to present my NephMadness abstract during an oral presentation. What an honor. I don’t have any photos but I did a screen cast of the presentation:

Nephmadness Unplugged is available here.