The Nephrology Social Media Collective Internship (NSMCi) is looking for interns. The NSMCi is a year long social media training program. It is not an introduction to social media, we expect some basic knowledge of how to use a computer, engage in social media, and how to write. What the internship does is provide recurrent opportunities to be public physicians.
You will learn how to creatively and effectively use Twitter to communicate. You will learn how to create visual abstracts. You will get involved in the inner workings of NephMadness. You will become familiar with every aspect of NephJC and produce summaries of articles, curated summaries of chats and even run the @NephJC account for a chat.
But listing the opportunities the the NSMC internship provides, misses the most important part of the internship. Joining the NSMC means joining a community of people that care about the field. You will get to work and learn from a motivated, international cohort of people who want to make nephrology and medicine better by sharing their knowledge and enthusiasm. This cohort is not just the faculty but also the interns themselves provide a lot of the insight, education and inspiration during the year.
Applications are due by the end of the year. The application is just a couple of questions and a CV. Be thoughtful with your answers. We read every one of them. Don’t think that because you are friends with Edgar Lerma you’ve got an inside line. (One of the first lessons of the internship is that everyone is friends with Edgar.)
We have been doing this for four years and we think the internship works best for nephrology attending and fellows, but we have had success with residents, nurses, PhD candidates, and medical students, but it is harder for them. We all speak fluent potassium. Be prepared.
During Kidney Week, the ASN sets up a daily podcast. This year, for the first time I was invited to participate on day three. I think it turned out pretty good. Give it a listen.
When we last left the anemia wars, the erythropoietin stimulating agents (ESA, which is Epo, Darbe, and CERA) were in full retreat. The ESAs had conquered ESKD and were (and still are) the standard of care to treat anemia. From that position they made a strategic strike on pre-dialysis CKD, targeting anemia in a larger slice of the world. There are 30 million patients with CKD, the market is big but relatively few of them have hemoglobin that is really low. Only 15% of patients with CKD have anemia, and that is using <12 g/dl in woman an < 13 g/dl in men.
One of the prominent theories at the time was to increase the hemoglobin to around 13 to reduce the cardiovascular disease that is so prevalent in CKD (remember the vast majority of these CKD 3 patients will die of heart disease long before they are even smelling a dialysis center).
This strategy was actually not a new idea. We had already tried this is dialysis patients. Besarab’s Normalization of Hematocrit was published in 1998. This showed that bringing the hemoglobin to 13 was bad in hemodialysis. It increased access failure, it nearly increased total mortality, and there was no signal of any benefit.
Despite Besarab’s red flag three randomized controlled trials were done to show that a high hemoglobin was beneficial in CKD, CHOIR, CREATE, and TREAT. All of them failed to show a benefit from the high hemogbin and all of them showed various, and not always consistent safety signals. The bottom line lesson of these three studies (four, if you include Besarab’s) was not to target a high (or even normal) hemoglobin with these drugs. The FDA recommended only using these drugs to avoid transfusions. KDIGO guidelines suggest a hemoglobin from 10 to 11.5 g/dl.
Nobody missed the top line result but the failure of normalization of hemoglobin also shined a light on the remainder of the ESA data. Erythropoietin was approved in the late 80’s for its ability to reduce the need for transfusions. But look as hard as you can you won’t find any data showing that treating anemia improved mortality. This is why the FDA limited use of the drug to prevent transfusion.
Those are quarterly transfusion rates, not annual.
The transfusion rate fell by two-thirds in the first year of widespread ESA use.
So that is how we left the anemia wars. ESAs retreated back to dialysis and there was a smaller amount of anemia treatment in pre-dialysis CKD to much more modest targets.
Since publishing TREAT and the revised FDA and KDIGO guidelines, anemia has slipped from the forefront of nephrology. The science has continued to mature and there is a new target, HIF-stabilizers (Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors). he HIF-stabilizers have been winding their way from the bench to the bedside for the last 20 years and are currently in the midst of large, long phase three trials. These trials are different than the approval trials for CERA, Darbe and Epo. Those drugs needed to show the ability to correct and maintane a stable hemoglobin. The HIF-stabilizers have to be at least as safe as erythropoietin. Just like diabetes drugs after Rosiglitazone, the FDA is no longer satisfied with an improved number. the drugs need to show cardiovascular safety.
That was the landscape in which two high impact trials on anemia were announced at Kidney Week 2018.
The first was Cardiovascular Safety of Methoxy Polyethylene Glycol-Epoetin Beta in Treatment of Anemia of CKD by Francesco Locatelli. This is a cardiovascular safety study of Mircera. It looks like the same type of trial the HIF-stabilizers are now undergoing to demonstrate CV safety. This is clearly a government request and so my criticism about the study may need to be directed at the FDA/EMA. What makes me uncomfortable with this study is the choice of control. Remember these are cardiovascular safety studies, but the epoetin was originally approved not based on cardiovascular safety but on the ability to avoid transfusion. In the only placebo controlled, cardiovascular trial of ESAs, darbepoetin alfa fell short of placebo.
In this latest Locatelli trial, Mircera was found to be as safe as ESAs that were previously shown to be inferior to placebo (at least at high hemoglobin and in diabetics, with pre-dialysis CKD). It is essential, if we are going to do studies assessing cardiovascular safety that they are compared to appropriate controls.
We should not be having patients spend years in a randomized trial trying to show non-inferiority to a drug that looks pretty inferior.
This is in opposition to the Intravenous Iron in Patients Undergoing Maintenance Hemodialysis study by Iain C. Macdougall. They showed that an aggressive iron schedule resulted in fewer transfusions, no safety signal and some real patient oriented outcome advantages (mainly hospitalization for heart failure and transfusions, which are especially important for patients waiting on a transplant list, i.e. almost everyone on dialysis).
Daniel Coyne, Author of the DRIVE and DRIVE II trials had a nice series of tweets about this trial:
If you went to a national nephrology meeting in the 2000’s and walked into a lecture on clinical AKI there were two obligatory sections that would be part of the talk.
The first would be how poor creatinine was as a marker for AKI. The expert at the front of the room would explain that creatinine was a lagging indicator and that by the time the creatinine had begun to climb the injury was yesterday’s news. Identifying AKI by a bump in the creatinine would force you to always be reactive rather than proactive. This discussion would then lead to a plea for better markers of AKI, followed by descriptions of NGAL, KIM-1, and other promising AKI assays of the future.The second would be a complaint about the lack of a consensus definition of AKI. The speaker would point to 35 different definitions of AKI in the literature, from highly sensitive (25% bumps in serum creatinine) to perfectly specific (need for acute dialysis during the hospitalization).
Depending on the exact year of the talk, they would then talk about the RIFLE criteria, or to the AKIN modifications to the RIFLE criteria, or to KDIGO’s modifications to AKIN. The speaker would always point to a future where we had a consensus definition of acute kidney injury so that we could start to move forward with a cohesive literature where one paper could be compared to another. What was always odd about these talks was that the second part of the lecture, about the emerging creatinine-based consensus definitions of AKI must have been browsing Facebook during the earlier part of the lecture about the futility of creatinine-based definitions of AKI.
But the consensus did emerge. Despite all the experts warning us about the problems with small changes in creatinine defining AKI, that is the world we live in. One problem with this definition recently emerged in a discussion of cardiorenal syndrome. This article by Testani et al found that:
The group experiencing hemoconcentration received higher doses of loop diuretics, lost more weight/fluid, and had greater reductions in filling pressures (p<0.05 for all). Hemoconcentration was strongly associated with WRF (OR=5.3, p<0.001) whereas change in right atrial pressure (p=0.36) and change in pulmonary capillary wedge pressure (p=0.53) were not. Patients with hemoconcentration had significantly lower 180 day mortality (HR=0.31, p=0.013). This relationship persisted after adjustment for baseline
We should not have a situation where increased risk of AKI (yes, I know the definition of worsening renal function, WRF, does not perfectly overlap with Stage 1 AKI, but work with me) is also associated with improved 180 day mortality. By defining AKI around changes in AKI we have deputized nephrologists to be the creatinine police and make decisions on treating patients based on what effect it has on short-term changes in GFR which may or may not have anything to do with long-term outcomes. In the above study, using serum creatinine to guide therapy leads to insufficient diuresis, poor fluid removal, and poor 180 day outcomes.
The Twitter discussion about this was particularly enlightening. Take a look.
Back in August, I went to Denver to spend a couple of days with the social media and communications teams at Davita. Davita headquarters is really cool. I loved getting a chance to peak behind the curtain into the inner workings of a professional communication team. I loved hearing the war stories of how they reacted and responded to the John Oliver dialysis piece. My overall impression was one of a well run and professional organization staffed by talented people. Dialysis mortality in the US has fallen 25% over the last 16 years. This didn’t happen by accident.
One of the highlights of going to Denver was recording a podcast with Dr. Provenzano (@DrBobPro). Robert Provenzano is one of my oldest mentors. I first met him as a first year fellow at the NKF Spring Clinical Meeting in Chicago. A year later he hired me to work for St Clair Nephrology, the practice where I am now a partner. He has been a constant advisor and advocate. It was a pleasure to chat social media with him.
One of the best medical bloggers is Robert Centor. He has been blogging since the flood (Don’t believe me? Here is his first blog post from May 19th, 2002) and beyond longevity he has been able to develop an enthusiastic engaged audience. He is both prolific and brilliant. I have had a few interactions withhim virtually. And we are RunKeeper friends so I keep an eye on his fitness. (He repeatedly trounces me in workouts-per-month).
Dr. Centor introduced me to The Curbsiders. When I saw that he was a guest on The Curbsiders, it was an instant badge of approval and I started listening. He also is, famously, the Chair of Medicine at Kashlak Memorial Hospital.
Last year he heard my diuretics discussion on The Curbsiders and invited me to participate in a podcast for the American College of Physicians. I said yes and then didn’t hear from him for almost year. Then he resurfaced and we recorded the podcast. Then another 6 months went by. I had forgotten about the thing and then last week the podcast dropped.
I think it turned out good (except for me saying medullary collecting duct when I meant cortical collecting duct. How embarrassing.)
The Annals On Call catalog of podcasts looks amazing. It is apparent that the slow pace I experienced was due to Dr. Centor building a deep catalog for his first season. Impressive work, but not unexpected from the guy who has been furiously blogging for 16 years.
The minds of OUWB continue to provide thoughtful questions.
My roommate and I have encountered a question regarding the content on Sodium/Water Balance and also its application to SIADH. We have been using some outside resources to supplement the learning in class, and I feel that they have been somewhat contradictory in these 2 scenarios. The following are the scenarios that I am trying to think through
1) Patient eats a high salt meal, increasing total body Na+, resulting in an increase in ADH release (via increased plasma osmolarity) and eventually reaching baseline Na+ concentration and osmolarity at a higher ECV. Now, the increase in ECV would result in a down regulation of Sympathetic NS and RAAS; however, what I am hearing is that this down regulation would just return the kidney to Na+ in = Na+ out and would not actually return the individual to the original ECV. So, my question is how does this person get back to original ECV? What I am reading is that the person will continue to operate at this higher ECV until sodium restriction takes place. However, I am wondering how decreased RAAS (decrease aldosterone – decrease Na+ reabsorption – increase sodium excretion) wouldn’t do this, and also if pressure natriuresis wouldn’t do this also? Basically, why don’t these mechanisms do the work automatically, and why do you have to sodium restrict?
You have it right. That is the currently accepted understanding of sodium metabolism. It is not quite complete, because, though some subjects increase their blood pressure with increased sodium intake, not all patients increase their blood pressure. As to why the renin-angiotensin aldosterone system does not down regulate itself sufficiently to fully correct the volume overload situation, it is not well understood. The sodium regulating systems in the body strive to match sodium absorption with sodium excretion. With an increase in sodium intake there will be a modest expansion of the extracellular compartment until the sodium excretion is upregulated to match sodium intake. We can see evidence of the increase total body sodium with an increase in body weight associated with increased sodium intake.
2) In SIADH – high levels of ADH cause increased water reabsorption but euvolemic hyponatremia. Fitting in with my previous questions in the earlier scenario, how does the patient maintain euvolemic status? If increased water reabsorption occurs and the ECV is increased, the same down regulation of Sympathetic NS and RAAS would occur. Now, the outside resources in this case state that a decreased RAAS would actually cause increased sodium excretion that would allow for increased water excretion that would maintain euvolemic status. This makes sense because then the hyponatremia that results is not only an effect of the dilution from increased water reabsorption, but also from the increased excretion of Na+. But, this goes directly against the whole logic of needing to sodium restrict in the earlier case (i.e. RAAS can’t do the work to return the individual in scenario 1 back to a normal ECV).
So again you are well versed in what is happening in SIADH. SIADH is largely euvolemic and largely is a situation where patients are in sodium balance, i.e. sodium = sodium out. However if you do meticulous metabolic balance studies you will find that patients do gain weight during SIADH. There is excess water and this does serve to expand the patient’s extracellular volume. This also will suppress the renin-angiotensin-aldosterone-system so that patients will get a modest increase in urine sodium excretion. But I don’t quite understand how you think this is any different than the first scenario. There is a modest increase in sodium excretion but in the presence of continued unremitting ADH activity the patient continues to deal with the modest increase in volume. So like the first scenario, the modulation of the RAAS is unable to fully restore euvolemia.
For more on SIADH and volume status see this post.
