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Twitter, Nephrology and the next version of the KDIGOmobile App

This summer, through luck and/or moxie I was able to land a plum position on the KDIGO team charged with building the mobile app. The team partnered with the crazy effective nerds at Visible Health to push out our initial vision. Our 1.0 for iPad was launched at ASN Kidney Week in Atlanta. Internally, we described the project as building a bridge across a gorge. This 1.0 is like a piece of dental floss connecting the two sides. It is an important step but it we have big plans for future versions.

We have received a lot of feedback on the initial release and the overwhelming requests are: Android, iPhone, Android, iPhone, Android, iPhone.

We are going to do both, but neither are the next step. The 1.0 version is essentially a PDF reader with all 9 KDIGO guidelines pre-loaded. Moving the app to Android and the iPhone will entail porting all of the guidelines to a new data model. We have a big vision for the product and are reworking the infrastructure to get there. Those two updates will come but they need to wait for the new data structure, for now, the only thing I can tell you is: Patience.

The current version of KDIGO Mobile has a community option that is a ghost town. We are going to tear that down and instead adopt the renal community on Twitter. The new social section will have a number of ways to view twitter that are designed to expose new people to the vibrant nephrology discussions that occur in there.

Users will have a number of twitter channels that they can tune into:

  • Current Twitter users will be able to view their timeline
  • Collecting duct: this is a highly selected list of twitter accounts consisting primarily of professional societies, journals and government organizations (Members | Timeline)
  • Proximal tubule: this is a highly curated list of users that typically provide intelligent nephro-oriented discussion  (Members | Timeline)
  • Glomerulus: this is a general list of every nephrologist and nephrology related organization I could find. (Members | Timeline)
  • Hashtags: this will be one or two hashtags that are of interest to nephrologists. For example, during next years Kidney Week, we would push out #KidneyWk14, during NephMadness we would highlight #NephMadness, We might leave #MedEd, #FOAMed, and #HCSM up at other times. etc.

All of these channels are stored on the servers at Visible Health so they can be controlled remotely and are eternally updatable.

Today, we are asking members of the nephrology social media sphere to look at the lists, try out the timelines, explore the hashtags. Tell us if we missed anyone or added someone undeserving.

When evaluating the timelines keep in mind the goal of these Twitter channels. We want to introduce new users to the utility of twitter for nephrology discussions. The timeline that I am most concerned about is the proximal tubule. The collecting tubule is an official channel and will likely be pretty dry. The glomerulus I think will be too much of a fire hydrant and I am thinking about dropping that channel altogether. I’m hoping that the proximal tubule can have relevant, compelling, content to really show off the utility of Twitter to naive KDIGO users.

Any and all feedback would be appreciated.

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Down goes SYMPLICITY.

SYMPLICITY-3 was Medtronic’s play to get into the hypertension business. They have a device that allows physicians to apply burn the sympathetic nerves of the renal arteries and lower the blood pressure. In a previous randomized trial it worked and SYMPLICITY-3 was what they were going to take to the FDA to get approval.

I started the day with our local hypertension guru explaining the inclusion criteria for Symplicity-4. An hour later this hit the wire:

Full press release

I was a huge fan of renal denervation and a bit of me died when the tweets started flying. Our local Symplicity PI says that the follow-up study with looser enrollment criteria, SYMPLICITY-4, has been cancelled. MedTronic supposedly is still going to carryout a trial of renal artery sympathetic nerve ablation in heart failure. If that is positive then it is possible the field will carry on, but if they abandon that, it may be lights out for the entire concept.

First CORAL, now SYMPLICITY 3. It’s been a bad couple of months for the renal arteries. They should get a better PR person.
— Joel Topf (@kidney_boy) January 9, 2014

Some thoughts on simplicity 3. The trial was on patients with severe resistant hypertension: office blood pressure over 160 on three blood pressure medications. These are hardcore hypertensives. This may not be an appropriate crucible to test the hypothesis of weather this works.

Thought two is that sympathetic discharge is thought to drive a lot of the hypertension in CKD and ESRD. (See this, this, and most importantly this editorial review)  So maybe when SYMPLICITY-3 excluded patients with GFR’s less than 45 they were excluding the very patients where the treatment would be most effective.
Thought three is that maybe in an effort to increase enrollment there were more inexperienced doctors doing the ablation. Unlike renal artery and coronary artery stenting there is no convenient sympathetic nerve ablation analog to TIMI-3 flow. At the end of the procedure the team has no idea if they successfully and adequately ablated the nerves. This could be a confounder. 
It will be interesting in subgroup analysis pif they find a signal pointing to efficacy being related to operator experience or a signal to better efficacy with worse GFR.
I blogged about SYMPLICITY here. Here is what Renal Fellow Network wrote about renal denervation when it was one of the top stories on 2010 and in an insightful post by Matt Sparks. 
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Fluid and Electrolyte Curriculum for Residency

I give monthly lectures to the residents at three hospitals. I bill the lectures as a comprehensive, year-long, fluid and electrolyte course. I have never established a fixed curriculum for the lectures, here is one take:

  1. Body water, IV fluids and diuretics
  2. Rapid interpretation of ABGs
  3. Acute Kidney Injury
  4. Osmoregulation and hyponatremia
  5. Hypernatremia
  6. Anion Gap metabolic acidosis
  7. Potassium
  8. Metabolic alkalosis and hypokalemia
  9. Non-anion gap metabolic acidosis
  10. Calcium and phosphorous and metabolic bone disease
  11. Electrolyte emergencies
  12. Board review practice
The curriculum starts with the basic mechanics that interns need to function in the hospital. How to order IVs, and intelligently use diuretics. This includes a review of body fluid compartments so that it is not just practical pearls but is based on physiologic foundation.
Electrolyte emergencies is a lecture that is not entirely written and needs to be. It would be a practical handbook style lecture to walk interns and residents through what I think is the best way to handle: metabolic acidosis and alkalosis, hypo- and hypernatremia, hypo- and hyperkalemia, hypo- and hypermagnasemia, hypo- and  hypercalcemia.
The introductory curriculum ends with the rapid interpretation of ABGs. After that I turn the intensity up a bit and focus on more physiologic based and less practical aspects of electrolytes. This allows deep dives on metabolic acidosis with separate lectures on anion and non-anion gap. I separate out metabolic alkalosis and potassium to provide time to do a deep dive on the monogenic causes of hypertension.
The board review session is a quiz session to review all the concepts of the year.
I have one spare month because a lecture always gets lost along the way.
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Kidney TREKS deadline approaches

Kidney TREKS is a program for medical students who want to learn about nephrology. Here are the components of the program from the website:

  • Attend the Mount Desert Island Biologic Laboratories “Origins of Renal Physiology” course for students, June 6-13, 2014. Tuition, travel stipend to Maine, room and board are paid by ASN.
  • Become connected with a nephrologist-mentor who will interact with the student over the course of medical school training, graduate school or postdoctoral fellowship.
  • Attend ASN Kidney Week during the 3rd or 4th year of medical school or graduate school with travel support (as a part of the ASN Program for Students and Residents).
  • Receive complimentary membership to the ASN with access to website resources for students.

To my mind, the first bullet point stands out as a once in a life-time opportunity. Mount Desert Island (by the way, best name ever: it’s a mountain, and a desert, and an island. Too bad they couldn’t get swamp and archipelago in there somehow) is a research lab where some of the seminal discoveries of renal physiology were made. My understanding is that the students have an opportunity to re-run some of the classic experiments with scientist mentors. Imagine a whole week of Kidney Science Camp.
I have not seen any reviews from participants from last year’s KidneyTreks but the reports from the fellow version make me want to re-do fellowship so I can go.
The deadline for applications is January 24th. Get to the link and apply now.
Imagine hiking around this beautiful island after learning the secretes of glomerular filtration.
Mount Desert Island Biologic Lab, home to the world’s nerdiest fence.
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Pseudohyperkalemia

The highest potassium I have ever seen? That would be 15.5 mEq/L.

It’s not real. It was pseudohyperkalemia from leukocytosis. The patient had chronic lymphocytic leukemia with a white count of 300,000. If you are not familiar with this condition, check out these posts on Renal Fellow Network: Westervelt and Nate. Nice full text references here and here (pdf).

The pseudohyperkalemia merit badge

The first time I saw this was when I was senior resident. I was sleeping in the call room my pager buzzed. It was the oncology floor with a potassium of 9. The patient had CML and was in a blast crisis. His leukocyte count around 100,000. I immediately suspected pseudohyperkalemia and ordered a whole blood potassium from the ABG lab. It was normal so I went back to sleep. The next morning I received an angry call from the Hemo-Onc fellow. The patient was coding and he was furious that I only ordered an ABG instead of treating the hyperkalemia.

I don’t know if the patient coded from hyperkalemia, but I wish that I had gotten out of bed and evaluated the patient. I solved the problem the nurses alerted me to, but if I assessed him, maybe I could of averted an arrest.

Regrets…

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Area Codes, RTAs, and Amphetamine. This is what Twitter is like.

Dallas is Area Code 214. I wonder if they appreciate that 214 really represents the 3 types of RTA in anatomic order?
— Joel Topf (@kidney_boy) January 7, 2014

This morning I was trying to imagine the mad electrolyte gurus of UT Southwestern in Dallas influencing the naming of the RTAs to match their Area code. Well played Donald Seldin, well played.

Not to be outdone, Dalya Munves joined in the area code and medicine game.

@kidney_boy other Dallas area code is 972, which is imprinted on amphetamine/dextroamphetamine tabs! #ADHDpride
— The Health Scout (@HealthScoutBlog) January 7, 2014

@HealthScoutBlog that’s why on the street they are call Ewings #ImMakingThisUp pic.twitter.com/sAVc4Wixvb
— Joel Topf (@kidney_boy) January 7, 2014

Any other area code-medicine mash-ups out there?

Note. The following 5 paragraphs from Douglas Coupland’s Microserfs that I read in 1995 has stayed with me since then. Love this minutia:

“Maybe. But let me digress a bit. Here’s something interesting . . . did you know you can figure out how important your state or province was circa 1961 by adding up the code’s three digits? Zero equals 10.” 

“No.” 

“It’s because zeros used to take forever to go around the little rotary dial-while ones zipped along quickest. The lowest possible code, 212, went to the busiest place, New York City. Los Angeles got 213. Alaska got 907. See my point?” 

Karla always comes up with the best digressions. “Yes.” 

“Imagine Angie Dickinson in Los Angeles (213) telephoning Suzanne Pleshette in Las Vegas (702) sometime before the Kennedy assassination. She dials the final ‘2,’ breaks a fingernail, and cusses a shit under her breath, irritated at Suzanne for being in a location with a loser area code.”

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2013 the year in review

2013 was a great year for the blog and for social media in nephrology. After a down year in 2012 for PBFluids, only 57 posts all year, I bounced back by nearly doubling that productivity with 112 posts last year. One of my most productive years. But to me the most remarkable change has been the emergence of a nephrology community in social media. My posts here at PBFluids certainly dripped with social media. Here is the year in review month by month.

January

Only 2 posts. I think the post on some slipshod research on NSAID toxicity in children stand up pretty well. The post included an embedded tweet from leading nephrology tweeter Pascale Lane.

February

8 posts. The first post is one of my favorite posts of all time. It is an analysis of the ISDA/AHA clinical practice guidelines on enterococcal infective endocarditis. The post is essentially a recap and summary of Twitter conversations on the subject with some additional research to provide some context. The remainder of the month has some solid work, including a post on dialysis for cast nephropathy bemoaning the lack of Gambro 1100 dialyzer availability in the US and a follow-up on the enterococcal post with a deep dive into additional data. Social poked through in a post on the horrible slides provided by the ASN by Myron Miller. I had a nice email from Paul Segal coming to Dr. Miller’s defense and a tweet from Jim Smith regarding the post.

March

March was my most productive month of the year. This was because I was researching NephMadness and working on a review of geriatric fluid and electrolyte issues (don’t hold your breath, it was rejected and will not be published). My favorite post of the month is probably this one about the NKF’s effort to get dialysis covered under medicare.

April

April was a very social month. I posted my first Storify (a web service that allows one to easily capture and publish a collection of tweets) on the link between hyponatremia and hip fractures. I had a few posts on Nephmadness (here, here and here). There was a nice post looking at over diagnosis as it relates to breast cancer, prostate cancer and CKD.  I had a patient show up with a potassium of 9 that led to a couple of posts on hyperkalemia. The image of the EKG is one of my most popular tweets ever. I used a poll on managing the hyperkalemia. Another favorite for the year, was a post about nephrology limericks. Again, this was primarily a summary of a twitter conversation.

@MGKatz036 Stop that NaCl its the reason he’s not doing well In order to volume resuscitate The hip new thing is Ringers Lactate
— Joel Topf (@kidney_boy) April 18, 2013

May

Another strong month. I tipped my hand about my Kidney Week poster by revealing some of the data on the nephrology blogosphere. My most shared story of the month was on NKFs poorly written story on alcohol and the kidney. PBFluids’ blade is still sharp. I had a couple of posts (here, here) on App.GoSoapBox.Com as I tried to incorporate this audience response system into my lecture. And a post with a screen cast on hyponatremia due to SIADH.

June

June had a number of social posts. I received a lot of commentary on a post about paying for kidney donors. There was some good discussion about my case of rhabdo with a CPK  over a million. But by far the most commented post was about the fool who drank a quart of soy sauce and developed severe hypernatremia. It resulted in two posts and another google docs poll. I also did a nice post on the Central American CKD epidemic that came after I was tweeted about my thoughts on the issue.

July

July was a light month, as I began to gear up for the second year medical students. I did publish my electrolyte handbook as an eBook. A project that I hope to spend more time on this year.

August

The big event in August was not on my blog, but on Twitter where I live tweeted the ASN Board Review Class. Awesome experience. I tweeted using the eAJKD account. Unfortunately eAJKD and I were just getting our live tweeting sea legs under us. We missed the important step of compiling the tweets into a blog post. I find that live Tweeting, focuses me and forces me to rework the information into a tweet. This helps me remember the information better. 

September

 

I went to London and live tweeted the Med 2.0 conference for eAJKD. Getting better at this. The blog had two posts where I used single tweets as jumping off sites for more extensive coverage, a model that I think best illustrates the purpose of a blog in a Twitter world. The first was on oliguria and the second was on the practice of giving patients money to help them buy medications, or in this case a treadmill.

October

Only 6 posts but a lot of impact. The month began beating back the idiots suggesting IV contrast is benign to the kidneys. I took the boards that month and posted my thoughts on the test and the ASN Board Review Class. The longest and one of the most important posts of the year was next. I posted on the CJASN electronic journal club. This has been a failure up to now. I hope that in 2014 this project can be re-invigorated. We will see.

November

I posted on the FDA’s terrible decision to deny Tolvaptan for ADPKD, following Bill Brazell’s brilliant essay in the Atlantic. We also had some fun guessing the retail price and possible names of the novel potassium binder,  KS-9. I posted on my Kidney Week experience. This was the first time I think Kidney Week really broke through on Twitter with a number of voices. It was a great success. I rounded out the month with an in-depth review of UKidney’s well done library of high-impact nephrology articles.

December

December was dominated by the Renal Fellow Network’s annual top nephrology stories of 2013 (see here, here, here, here and here). This turned into a collaborative effort as a lot of independent nephrology bloggers and participant in social media began to blog about different stories. I hope 2014 turns into the year when we really see more collaboration in the Nephrology Social Media Space. I think the RFN top stories offers a blue-print for this. The other post that was particularly social was an examination of an abstract linking Pip/Tazo to acute renal failure. A lot of twitter discussion on this.
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Another Candidate for Top Nephrology Story of 2013: HDPAL

Another guest post, this by Christos Argyropoulos of Athens. You know him on Twitter as @ChristosArgyrop.

Lisinopril vs. Atenolol for hypertension in the dialysis unit

Background and Rationale 

A study reporting the relative effectiveness of lisinopril over atenolol for hypertension in the hemodialysis unit was presented in the 2013 Kidney Week meeting. The HDPAL (NCT00582114) was a parallel group, open label randomized control study conducted between 2005-2013 in a single center that was sponsored by IU and supported by NIDDK. The aim of HDPAL (per the clinicialtrials.gov entry) was to “directly test the hypothesis that an initial strategy of lisinopril-based therapy will be more effective than atenolol-based therapy in causing regression of LVH over one year in patients with hemodialysis hypertension despite similar degree of BP reduction”. The justification for the study was provided by the high prevalence (>80%) of hypertension in the dialysis unit and the associated morbidity of stroke and left ventricular hypertrophy, while the choice of interventions tested in  HDPAL  was motivated by prior pilot studies performed by the PI in the late 1990s. These studies showed that atelolol and lisinopril are both able to reduce monitored ambulatory blood pressure (ABPM) to a similar extent i.e. by  ~20/11 when dosed three days a week after dialysis in a supervised fashion.

Study Procedures and Outcomes 

HDPAL randomized HD patients with echocardiographically documented LVH to either atenolol (initial dose: 25mg TIW, titrated to a maximum of 100 mg by doubling the dose q2wks) or lisinopril (initial dose: 10 mg TIW titrated to 40 mg by doubling the dose q2wk). To be eligible to participate, patients with LVH had to either have an ABPM > 135/75 (after a UF trial), or not be receiving any antihypertensives if they did not want to participate in a UF trial. Felodipine (10 mg) could be added once the maximum dose of the study medications had been reached and other anti-hypertensive agents could be added after felodipine if ABPM did not decline below 140/90. 
The primary outcome for the study was regression of LVH by echocardiographic criteria at 12 months, while secondary outcomes to be assessed were regression of LVH by echo at six months and the adjusted (for age, gender, ABPM) index of LV mass/BSA from baseline to month 12.
Patients would have echocardiographic assessments at baseline and again at 6 and 12 months, as well as ABPM at baseline and 3, 6, and 12 months and were also asked to self monitor their BP.

What did the study show?

The study enrolled 200 (mostly African American) patients, but it was stopped prematurely for safety reasons so that only 104 patients completed follow-up (58 in the atenolol and 46 in the lisinopril arm). At the time the study was stopped, patients on atenolol had numerically higher reductions in LVH but this finding did not reach statistical significance. The safety signals were ubiquitous for patients on lisinopril:
  • Excess number of serious cardiovascular events(IRR: 2.36, 95% CI 1.36 to 4.23, P=0.001) 
  • Excess major cardiovascular events (IRR 2.29 95%CI: 1.07-5.21 p=0.02)
  • More frequent hospitalization for all causes (IRR: 1.61 p<0 .01="" li="">
  • More frequent hospitalization for congestive heart failure (IRR 3.13 p=0.02)
  • More likely to develop hyperkalemia (IRR 3.38 p=0.05)
  • More likely to suffer a hypertensive crisis (IRR 3.81 p=0.03)

On the other hand, atenolol was more efficacious in reducing BP, irrespective of the method of assessment (ambulatory v.s. home self-monitoring) by 3.5 and 6.3 mmHg respectively). These patterns of suboptimal BP control by lisinopril were noted despite more aggressive fluid removal and a larger number of additional blood pressure medications.

Discussion

As the study was terminated prematurely, the primary and secondary end points could not be fully assessed and the superiority of beta blockers versus ACE inhibitors remains an open question. On the other hand, the reported patterns of blood pressure reduction and the cardiovascular safety signal were surprising given the established track record of ACEis in reversing LVH and the poor relative efficacy of atenolol against other agents in the non-ESRD population (Cochrane Database Systemic Review, though not everyone agrees with this interpretation e.g. Blood Pressure, 2007 and BMJ, 2009). However tempting it may be to attribute these findings to a play of chance, or undifferentiated secular trends (e.g. the study was registered with Clinical Trials.gov in 2005, yet only 104 patients had a year of follow-up by 2013) the possibility that atenolol is indeed a better drug than lisinopril for dialysis patients with LVH should be entertained. Working under this hypothesis, there are at least two possible explanations for the apparent benefit of atenolol on blood pressure control:
  1. A ghost of studies past: A number of studies have suggested that African American patients with cardiac disease (either LVH or systolic dysfunction) may respond better to beta blockade compared to RAAS inhibition (a pattern seen in the Losartan Intervention for Endpoint Reduction – LIFE study), or even receive no benefit from ACEs compared to whites (e.g. SOLVD). Considering that the mostly African American participants in HDPAL were on the ultimate “diuretic” (dialysis to dry weight), an intervention that diminishes the relative (in)effectiveness of beta blockers in the non-ESRD African American population, one could hypothesize that the results of this study may reflect a racial benefit of beta-blockers for African American with LVH. It would be interesting to see whether the investigators of the HPDAL broke down the results according to race, as a hypothesis generating analysis.
  2. Pharmacokinetics: Atenolol and lisinopril pharmacokinetics on dialysis differ and these differences may explain the inferior blood pressure control in home and ABPM recordings. While both agents are efficiently cleared by hemodialysis, with apparent intradialytic half life between 3.5-5 hrs  (atenolol: BJCP, 1980, Arch Toxicol Suppl, 1980 and Eur J Clin Pharmacol, 1981, Hemodialysis International 2013 and lisinopril BJCP, 1988) there are important differences in the time to the peak (~4hrs with atenolol, 8-44 hrs with lisinopril) and rebound kinetics (larger rebound with atenolol). Based on these considerations one could hypothesize that patients receiving atenolol in the dialysis unit would spend a much shorter period of time under-medicated as a result of the faster absorption of the drug and possibly its higher rebound. This could explain the larger time difference in BP noted in ABPM recordings and home BP measurements. To the extent the investigators obtained blood levels, it might be possible to explore the pharmacokinetic hypothesis by correlating free drug concentrations to ABPM or home BP recordings. To the extent that pharmacokinetics play a role in explaining the HDPAL results, one could consider using alternative RAAS inhibitors (e.g ramipril) that are exhibit more comparable kinetic behavior to atenolol.

Implications for clinical practice

This is an interesting pilot report about therapeutic intervention to control hypertension in dialysis, a common problem for our patients. Current approaches to this problem are unsatisfactory, judging from the frequency with which nephrologists switch agents (BMC Nephrol. 2013) in the unit. Far from definitively proving the superiority of beta blockers over ACE inhibitors due to the limitations of a prematurely stopped and thus underpowered study, HDPAL adds some important information that could help clinicians choose blood pressure medications for their dialysis patients. In particular, HDPAL suggests that the perceived inferiority of beta blockers in the non-ESRD population may not apply to dialysis patients. Though it is customary to say that further studies will be needed (and in fact we do need them!), clinicians managing hypertensive dialysis patients should lead by example and consider applying the HDPAL protocol in the context of “n=1” trials. These studies “consider an individual patient as the sole unit of observation” to investigate the efficacy or side-effect profiles of different interventions (Per Med. 2011). In particular, rather than switching antihypertensives around in no systematic pattern, the nephrologist working with the patient under a shared decision making paradigm carry a structured evaluation of lisinopril (the most commonly prescribed ACEi, used in 20.9% of dialysis patients) vs. atenolol (the least prescribed beta blocker, but still used in 7.2% of patients) correlating home blood pressure (or ABPM if available) in a 4 period crossover fashion. By pooling multiple such studies it may be possible to fill in the knowledge gap that HDPAL tried to fill. 
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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.