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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.

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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.

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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.

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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.

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So now that we know that ZS-9 lower potassium, how much do you think it will cost?

One of the only positive trials at Kidney Week’s Late Breaking Trials Session was ZS-9, a novel potassium binding crystal that hopes to take the place of Kayexalate (Sodium Polysterene) in the hyperkalemic cocktail.

I wrote about the trial for eAJKD and was quoted in an article for MedPage Today.

Here is the skinny:

  • ZS-9 uses potassium specific pores to bind potassium rather than a cation exchange resin. It is highly specific for potassium, especially when compared to SPS.
  • In the phase 2 trial 10 grams lowered the potassium by 0.04 mEq/L per hour
  • In the phase 3 (753 patients!) trial the 10 gram dose lowered the potassium 0.78 mEq/L in 14 hours
  • No diarrhea
  • GI side effects were equal in the placebo and drug arms
I suspect this drug is on a smooth glide path for approval. My question is how expensive will it be? My guess is $200 per 10 grams. Please add your guess or over-under bet to the comments or @kidney_boy on Twitter.
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Tolvaptan, ADPKD, and lack of vision at the FDA

About a year ago the ASN Kidney Week hosted the most exciting Late Breaking Trial Session I have attended. The session included the first public disclosure of the EVOLVE trial and the incredibly exciting results from the TEMPO 3:4 trial. I blogged about this for eAJKD and felt then, and still feel now, that this was an incredible breakthrough for nephrology. Unfortunately that announcement may ultimately be the high point for tolvaptan. In April the company acknowledged previously unsuspected liver toxicity. Then in August the FDA denied the application for an indication for ADPKD. Tolvaptan is still approved for hyponatremia and doctors can always prescribe the drug off label but the drug is so expensive I think few patients will be able to get it approved by their insurance companies leaving them to face the $273,000/year bill alone. I always suspected that Otsuka would change the price of the drug when they got a second indication for the drug that changed it from a short-term, in-house drug to a chronic out-patient indication. We may never know.

This is the second significant set back for tolvaptan. Otsuka had investigated it for heart failure with the flawed (in my mind) Everest Trial. Tolvaptan never sought an indication for heart failure because their trial was negative. This is what makes the FDA’s decision so upsetting, the TEMPO trial was positive, the drug met its primary end point (P=0.001), it slowed cyst growth. The secondary end-point, and more clinically relevant end-point, of decreased change in GFR was also positive (P=0.001).

Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P=0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P=0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P=0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).

Side-note about the choice of change in kidney volume rather than change in GFR for the primary end-point: This was used because ADPKD is such a slowly progressive disease that investigators feared if a treatment was required to slow the change in GFR, it would be prohibitively expensive and slow to evaluate therapies. The change in kidney volume was adopted by the ADPKD research community as an acceptable intermediate end-point after observational imaging studies found a tight relationship between change in kidney volume and renal prognosis.

When I heard about the denial  I figured the liver toxicity must have much more severe than I suspected. That turns out not to be the case. Bill Brazell (Bill is a former board member of the PKD Foundation and reader of PBFluids, who was at the FDA hearing) described the liver toxicity founding the TEMPO trial:

A small number of patients experienced potentially important elevations of liver enzymes (4.9 percent, compared to 1.2 percent of those who took a placebo), but the panel focused for hours on the simultaneous elevations in both liver-enzyme levels and bilirubin that occurred in just three patients out of the 860 who took the drug. In all three, the elevations occurred within 18 months. After those patients stopped taking tolvaptan, their levels returned to normal. No one suffered permanent damage

Certainly tolerable to my eyes, especially considering the health implications of dialysis and kidney transplant.

The thing that frustrates me the most is that there are no other proven treatments. We have nothing to offer our patients that works, the only effective therapy was denied approval. Silly FDA what do they expect these patients to do?

I hope Otsuka stays the course, provides additional outcomes data so we can get this approved and I hope the FDA opens it’s eyes and begins to see that in the absence of perfect we should accept good.

The article I linked to by Bill Brazell is an excellent discussion of the same issue from a patient perspective. Read it.

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Calling all Apple nerds! See if you can predict what will be announced…Updated!

Apple already announced new iPhones and has a media event scheduled for October 22nd. If you think you have some Apple game see if you can predict the announcements. Go here to fill out your entry. Voting ends Tuesday morning.

UPDATE
The winner is…Milos who crushed the competition with a score of 40! He correctly nailed the price of the price of the two iPad minis, the camera specs of both new iPads, almost perfectly nailed the specs of the iPad Air (only blemish predicting an A7x rather than the A7). But where he really lapped the competition was predicting that the program would ignore the iPods and Apple TV. Strong work!

Second place was Steven with 30 points. I tied for fourth with Mhallang at 28 points. Thanks for playing.

You can see all of the submissions here.

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Kidney Week Approaches!

This year for the first time (that I am aware of) Kidney Week is in Atlanta.

I was lucky enough to get both an abstract and oral presentation accepted. Both are on social media.

The Oral presentation is on the lessons from NephMadness. I will be speaking at 5:30 on Friday, November 8, in Room 409. The session is titled Nephrology Education and Research and runs from 4:30 to 6:30.

The poster presentation is on Thursday November 7 from 10 to 12. The poster is a review of productivity, longevity and consistency in nephrology blogs. It is poster number TH-PO880.

I would love to meet any readers of the blog, so stop by. Also if you post your abstract/poster information as a comment to this post I will make every effort to visit your poster and review it on PBFluids.com from a design and nephrology perspective. Think of it as The Blogger Eye for the Scientist Guy.

See you in Atlanta!