Boy, our fellows are smart!

The St. John Hospital and Medical Center has a nephrology fellowship where I am on the teaching staff. We currently have a particularly talented cohort of fellows but I had no idea how that talented compared on a national scale.

We just got the results of the Nephrology In-Service exam and our crew hit it out of the park. The average score was 69, only 4 programs (with five or more fellows) scored higher. Congratulations guys!

Pharma and Medical Education

Jose Arruda, Chief of Nephrology, UIC Medical Center

I was excited to see Dr. Arruda on the schedule to speak at our fellowship. This is one of the best aspects of being an academic nephrologist; we get prominent nephrologists from around the country to speak to our department.

When I saw the title of his lecture was A New Approach to Hyponatremia, I knew we were going to get the vaptan story (PDF).

Otsuka is pushing tolvaptan (Scamsca™) hard. We are getting detailed a lot, and I hear that the cardiologists are also getting an earful. Honestly, the data looks a little thin to me. The drug is the most reliable method for tackling persistent SIADH. But that's rare. In my experience, usual care fixes almost every case of hyponatremia within a day or two. There are a minority of cases that don't respond quickly. These episodes of persistent hyponatremia worry me. Unfortunately, tolvaptan doesn't feel like a good option for these patients. We know from the SALT studies that a week after you stop the drug the sodium equals the control group and the drug costs $300 per day (average wholesale price (PDF), retail price). I find it hard to prescribe a $9,000 per month drug for chronic therapy. I'll stick with salt tablets, furosemide and water restriction.

Arruda's lecture was on tolvaptan and the first slide was giving some background on hyponatremia and he commented that "I hate this slide." I can't imagine putting together a presentation and flying 500 miles to present it and loathing the very first slide.

It is illustrative of what is wrong with academic nephrology. Dr. Arruda hates the first slide in his deck. Why doesn't he remove/fix/change the slide? Because the slide deck has been vetted by the FDA and Otsuka's lawyers. He can't change it. He has signed a contract saying he won't change it. Dr. Arruda gave a solid, thoughtful lecture to our department, but he did that in spite of the materials he was using. He spent considerable time just talking about the pathophysiology of sodium and did a better job than most at avoiding being a mere shill for Otsuka.

Our nephrology program, and I suspect others (most?) rely on the generosity of pharma companies to bring scientists to our program but we pay by letting the drug companies supply the slides. Tragically, those slides are vetted by people uninterested in education and devoted to meeting the conflicting demands of both the marketing and legal departments.

Dr. Arruda seems like a good guy and is a highly respected nephrologist but the only way we could get him to come to Detroit was on Otsuka's dime and they were able to control the message.

Dose of DIalysis

Everything I learned in fellowship has turned out wrong. When I was a fellow I was taught:

• Higher Kt/V were beneficial for patients
• Increasing the hemoglobin reduced LVH and improved outcomes in CKD
• Using non-calcium based binders saved lives
• and most importantly: increasing the dose of dialysis in AKI improved survival
  

The last point was an area that was emphasized in my education. I heard Dr. Murray spend so much time going over the preliminary evidence that I was honed to proselytize the gospel of early and often dialysis for acute kidney injury. I loved working with Murray, he's a great speaker, a great teacher and the only man with more board certifications than years in middle school (internal medicine, nephrology, critical care, clinical pharmacology).

Since finishing fellowship it has been humbling watching each of these truths fall to the blade of the RCT (though I still believe that calcium based binders are harmful).

The results of the ATN Trial this past summer has been especially heartfelt because I was so invested in the outcome. I had argued and fought so many times to get an access and initiate dialysis, to get an extra-treatment, all this time being smugly self confident that I was helping the patient. Confident that I was fighting the good fight. Ughh.

So here it is, a review of the article that kicked me in the chest...
The objective was to determine if more intensive dialysis for acute kidney injury would improve survival in critically ill people. Unique to this trial, the protocol allowed patients to get either conventional hemodialysis or hemofiltration depending on the hemodynamic status of the patient at any time during the trial. This innovation allows the trial to better track actual practice. Additionally, it allows the trial to get past the eternal debate of which modality is better, and answer the question of what dose to target regardless of the modality.

The study was conducted from 2003 to 2007.

The trial was run at 27 institutions.

Enrollment criteria:

• Critically ill adult
• Age: 18 or older
  
• Renal failure plus at least one other organ system failure or sepsis
  

Patients who were hemodynamically stable were provided hemodialysis (prescribed Kt/V 1.2-1.4). If they were unstable, CVVH or SLED was provided. The decision between CVVH and SLED was determined by individual site preference.

Patients were randomized to one of two dosing schemes:

Less-intensive strategy:

• Stable: Intermittent hemodialysis: 3 days a week effluent
• Unstable: Continuous therapy: effluent of 20 mL/kg/hr

Intensive strategy:

• Stable: Intermittent hemodialysis: 6 days a week effluent
• Unstable: Continuous therapy: effluent of 35 mL/kg/hr

These definitions for dose come from Ronco's paper (continuous therapy) and Schiffl's paper (intermittent therapy) two studies which are (were?) frequently invoked as support for high dose dialysis in acute kidney injury.

Dialysis was continued until recovery of renal function, discharge from the ICU or 28-days of therapy or death. Recovery of renal function was defined by 6-hour CrCl of >12 mL/min and investigator discretion or >20 mL/min.

Primary Endpoint: All-cause mortality at day 60.

Secondary endpoints:

• In-hospital death
• Recovery of renal function (CrCl>20). Recovery was defined as complete if Cr was <0.5>0.5 over the baseline creatinine.
• Duration of renal replacement therapy
• Dialysis free at 60 days
• Duration of ICU stay
• Return to previous home at day 60.

Power analysis

• Estimated mortality with less-intensive strategy 55%
• Estimated mortality with intensive strategy 45%

The authors estimated 10% loss to follow-up and all patients lost were assigned to "alive" for analysis. 90% power with a sample size of 1164.

Enrollment was below the power analysis goal of 1164 at 1124 but the study had better retention with 29 being lost for various reasons and 5 being lost and analyzed as "alive." The power analysis anticipated 112 people being lost.


The all important table 1. shows a cohort that looks similar to the patients I take care of. 60% sepsis and 80% ventilated. Appache 26. All and all, a sick cohort.

The protocol was adhered to extremely well with extra treatments occurring on 0.5% of days in the high dose group and .5% of days with less-intensive strategy. Missed treatments occurred on 1.9% of days in the intensive strategy and 1.1% in less-intensive strategy. Surprisingly, the delivered dose of dialysis with intermittent therapy was a Kt/V of 1.3, right in the middle of the prescribed target. ICU patients are classically difficult to dialyze and previous analysis of delivered dose have shown it to lag well behind prescribed dose.

With continuous therapy the delivered dose like-wise correlated well with prescribed dose: 36.2 mL/kg with intensive strategy and 21.5 mL/kg with less-intensive strategy.

Primary outcome: 53.6% 60-day mortality with less-intensive strategy and 51.5% mortality with intensive strategy (p=0.47).

Secondary outcomes:

• In-hospital mortality: 48.0% less-intensive strategy, 51.2% intensive strategy
• Complete recovery of renal function (day 28): 18.4% less-intensive strategy, 15.4% intensive strategy
• Return to home by day 60: 16.4% less-intensive strategy, 15.7% intensive strategy

Complications: Patients on the intensive strategy required vasopressor support during renal-replacement therapy more often, 14.4% vs 10.0% (p=0.02) and required interventions for hypotension more often, 37.7% vs 30.0% (p=0.006). However, in intermittent dialysis both groups reported similar rates of dialysis associated hypotension 18.5% with intensive vs 18.0% with less-intensive) and similar drops in blood pressure (MAP from 86 to 75 with intensive and from 86 to 74 with less-intensive). The increase in dialysis associated events maybe related to the increased frequency of dialysis (more exposures to dialysis) with intensive strategy.

Hypophosphatemia (17.6% vs 10.9%, p=0.001) and hypokalemia (7.5% vs 4.5%, p=0.03) were both more common with intensive therapy than with less-intensive therapy.

The editorial by Bonventre that was published with the article was okay. I would re-direct interested readers to the Hume, et al. editorial in AJKD which was better.

Some points from the Bonventre article include:

• Increased numbers of men in the study
• Lack of CKD patients
• Questions about the changing of modalities allowed by the protocol
• Increased amount of SLED in the intensive therapy group compared to the less-intensive strategy

Some choice quotations from the Hume article:

This report currently should be viewed as the definitive study defining dialysis dosing in critically ill patients with AKI.

During the maintenance phase of AKI, while hemodialysis/hemofiltration techniques are being utilized, the patient dies from multi-organ failure while in exquisite electrolyte and fluid balance.

Our group has focused on 2 major areas of evaluation. The first is the recognition that current renal substitution therapy only provides the small-solute clearance function of the kidney but not the metabolic and endocrine functions of the kidney. Similar to the clinical evidence that kidney transplantation markedly prolongs survival and improves health related quality of life compared to dialysis, the replacement of renal parenchymal cell functions in AKI may change the natural history of this disorder.

Nephrology Fellowship: by the numbers

We have come to that time once again. Time to interview a gaggle of highly qualified candidates for a few spots in our nephro fellowship. Here is is how it looks by the numbers:


The number of new nephrologists is just under 400 per year.

30% are woman and 51% are US medical graduates. This is a decrease in the number of foreign medical grads from 50% in 1999 to 40% in 2005.
757 applicants applied for 372 spots in at 135 accredited programs in 2007.

Nephrology is the fourth most popular internal medicine sub-specialty after cards, Heme/Onc and Pulmonary/Critical care (look at the bottom of the list and add that to the combined Pulm/Crit Care).

42 kidney transplant programs are available.

There are 19 programs in interventional nephrology however, only 6 are certified by the American Society of Diagnostic and Interventional Neophrology (ASDIN).

More info.

From the trenches of the consult service...

Me: If a bicarb of 6 and an anion gap of 35 doesn't get you excited you shouldn't be a nephrologist.

My fellow: Yeah, its the ST-elevation MI of nephrology.

Fellow talk: interesting case

Dr. Dhungal did the interesting case conference this morning. He did a great job.

Primary Hyperadosteronism

View SlideShare presentation or Upload your own. (tags: aldosterone hypertension)

Former Felllow makes good

Rakesh Lattupalli just graduated from our fellowship in June. He was an exceptional fellow. He just finished a scientific article on the Melamine outbreak. Rakesh was the person who got me interested in the subject. The article is a nice overview of some of the scientific data on melamine toxicity.

Like me, he feels that melamine is not likely to be the entire story and a second co-factor will be identified that is critical to the development of nephrolithiasis. He suggests cyanuric acid as a possible candidate.