Great article on the Nesiritide debacle

There has been some great articles regarding the expensive, waste of a decade induced by nesiritide.

I like this article the most because it's written by someone who is not in medicine. It tackles many of the same issues I looked at in my post, The problems with numbers, namely when drugs are approved based on intermediate end-points bad things can happen.

The best thing we can say about niseritide is that when the definitive trial was finally done, the previous concerns about renal failure, were shown to be merely illusions created by the smoke and mirrors of meta-analysis.

Acute renal failure was an early concern regarding Nesiritide...

...but when the right placebo controlled trial was done, no renal failure.

So go and read Carolyn Thomas' view of nesiritide and see how we have failed the people we are entrusted to care for.

Cardiorenal syndrome

On the first Friday of every month I give a lecture to the residents at St. John Hospital and Medical Center. I like to do an electrolyte lecture but for March the chief resident asked me to talk about cardiorenal syndrome. In researching the lecture I came across this article by Claudio Ronco.

The article defines cardiorenal syndrome as any condition with simultaneous kidney and heart failure. He then goes on to subdivide cardiorenal syndrome into 5 types:

1. Acute heart failure causing acute renal failure
2. Chronic heart failure causing chronic kidney disease
3. Acute kidney injury causing any type of acute cardiac dysfunction (including arrhythmia)
4. Chronic kidney disease causing any chronic cardiac disease
5. Any systemic condition that causes renal and cardiac dysfuction (e.g. sepsis)

This is terrible. Cardiorenal syndrome used to signify the unique cause of acute kidney injury where the decrease in function is due to apparent volume depletion in a patient that obviously overloaded. It named the only scenario where acute kidney injury responded to diuresis. It was unique and specific. Ronco comes along and says, yes I like your version of cardiorenal syndrome so I will make it type 1 in my new all purpose definition of cardiorenal syndrome. Now whenever there is cardiac dysfunction and simultaneous kidney dysfunction we can just call it cardiorenal syndrome.

It doesn't have to be this way look at the example of hepatorenal syndrome. The syndrome does not refere to just any situation with simultaneous renal and liver dysfunction. It is a very specific diagnosis that only occurs with chronic liver disease and ascites. The patients must be oliguric, there is no non-oliguric HRS. Patients must be sodium avid and unresponsive to fluids and albumin. Additionally the patients cannot have laboratory or imaging evidence for an alternative cause of renal failure. Because of this definition hepatorenal syndrome identifies a very specific disorder, with a specific pathophysiology and unique prognosis and treatment options.

Ronco takes the beautiful and evocative name cardiorenal syndrome, strips it of all specificity and then tries to restore it by tacking on five different types. The fifth type 5 is the one that makes my brain explode. Sepsis, really? Acute kidney injury from sepsis that happens in the same patient who also suffers from sepsis induced cardiomyopathy should now be considered to have cardiorenal syndrome? Ronco is a man who has spent his life studying sepsis and acute renal failure, I can't believe he is actually referring to that condition as CRS type 5.

I'm not buying what Ronco's selling. Cardiorenal syndrome begins and ends with type 1 for me.

FYI: Here is the lecture (Keynote, PDF). It still needs some work. I'd like to add a section on ultrafiltration and I need to include the NEJM article on furosemide that was published yesterday.

Journal Club: Aspirin and FGF-23

The first article was an intriguing look at various renal function parameters and how they respond to various doses of aspirin. All the patients were pre-treated with enalepril and a thiazide diuretic for 6 days. Then they were given one of four doses of aspirin:

1. placebo
2. 80 mg
3. 160 mg
4. 320 mg

They found decreased GFR, decreased sodium clearance, decreased solute clearance and decreased free water clearance with 160 mg and 320 mg but the effect was transient with all factors returning to baseline 4 hours after the aspirin was administered.

The article has a long introduction and discussion outlining all of the heart failure studies which have shown that aspirin can be harmful or can decrease the effectiveness of ACEi in heart failure.

The study is small (n=16, with each participant randomized to two doses of aspirin with a 2 week washout between doses) and the authors fail to fully describe the cohort. The primary weakness is the authors want to extrapolate there findings over 6 hours to the effect of aspirin taken chronically for years. Additionally they make the leap of using aspirin-induced changes in renal function to be a proxy for interference with ACEi effect on heart failure survival.

Nonetheless it will change the way I practice. I had previously given my patients (who essentially all are on diuretics and ACEi) the green light to take aspirin any way they want. I will now suggest they limit themselves to 81 mg for CAD protection.

The second article was the NEJM article on FGF-23 and the risk of mortality in hemodialysis patients. FGF-23, or fibroblast growth factor-23, is a newly discovered molecule which regulates the phosphorous in the body. It is one of the primary phosphatonins, signals which increase the renal excretion of phosphorous. Additionally they suppress 1-alpha hydroxylase lowering the amount of 1,25 dihydroxy-vitamin D.

This is prospective cohort with nested case-control of incident dialysis patients in the U.S. The investigators looked at 200 patients who died (cases) in the first year and compared them to 200 patients who survived one year (control). FGF-23 was measured on the first day of dialysis. They divided the cohort into quartiles based on phosphorous and found that patients who subsequently died had increased FGF-23. They found a graded increase in the risk of death with increased FGF-23 level that was signifigant in the whole cohort and inevery quartile of phosphorous except the highest.They also showed a dose responce of mortality to FGF-23 levels in the whole cohort in the crude data, case-mix adjusted and multivariate adjusted.


The authors in the discussion point out that the association of FGF-23 with mortality is stronger than that found with phosphorous and mortality. They found FGF-23 levels were 22% lower in African-Americans than in Caucasians. The authors leave a tease that this lower level of FGF-23 level may explain the improved survival found in African Americans on dialysis.