Monday, January 11, 2016

Why is the FENa elevated in acute tubular injury?

Tonight there is a twitter chat on this article

The chat is at 9:00 PM EST, with hashtag: #JHMChat.

The paper is a good review of the weaknesses of both the fractional excretion of sodium and urea. I have a few critiques of the article but one in particular is too complex to express in a tweet, so time to fire up PBFluids once again.

Before we move on, a quick reminder of exactly what FENa measures:
Reminder of what the FENa measures, excreted sodium divided by filtered sodium

In the paper they describe why patients with AKI get an increased fractional excretion of sodium:
In normal health, FeNa is typically 1%, although it may vary depending on the dietary sodium intake. The corollary is that 99% of filtered sodium is reabsorbed. Acute tubular injury (ATI) that impairs the tubular resorptive capacity for sodium may increase FeNa to >3%. 
This view of the increased FENa of intrinsic renal failure envisions a world where the kidney needs to reabsorb approximately 99% of filtered sodium to remain in sodium balance, then when the tubules are damaged by acute tubular injury they fail in that job and begin to waste sodium.
The view of FENa as expressed in the article by Pahwa and Sperati

The problem with this model should be quickly obvious, intrinsic renal failure is not a sodium wasting state, in fact these patients have the opposite problem of sodium retention, fluid overload and hypertension. So we have a calculation that shows increased sodium wasting but we have a clinical scenario which shows sodium retention.

The way out of this paradox is that damaged nephrons do not waste sodium. When the tubule suffers acute tubular injury, filtered sodium (and chloride) fails to be reabsorbed in the proximal tubule and thick ascending limb of the loop of Henle. This flood of unreabsorbed chloride trips sensors in the juxtaglomerular apparatus and shuts down the glomeruli. This is the nature of tubular glomerular feedback (TG feedback).

TG Feedback in action. A failure to reabsorb Na (and Cl) means that excess distal delivery of chloride will trip the JGA and shut down the glomeruli.

It is also (at least) part of the reason the histologically intact glomeruli have a GFR of zero. The damaged tubule sends an SOS to the glomeruli telling it to shut down. If the tubules cannot reabsorb sodium it is essential that the glomeruli stop filtering. A kidney that filters but fails to reabsorb will pee the patient to death in a matter of minutes (GFR of 100 mL per minute will excrete all of the plasma volume in 30 minutes) The kidney (teleologically speaking) is programmed to never let this urinary nightmare happen.

So if in acute tubular injury, the damaged tubules do not provide the urine used to assess FENa, where does that urine come from? It comes from the intact nephrons. Remember acute tubular injury is a patchy diagnosis, with some regions of the kidney being affected and others being relatively spared. It is the unaffected nephrons that produce the urine in acute tubular injury that has the high fractional excretion of sodium. Why is that? It is best to look at what happens to FENa in normal patients as CKD progresses.

In a patient with a GFR of 100 ml/min and a sodium intake consistent with current guidelines, 100 mmol/day (2.3 grams sodium), the average fractional excretion of sodium will be:

  • Excreted sodium = daily sodium intake = 100 mmol/day
  • Filtered sodium = 0.1 L/min x 140 mmol/L x 1,440 min/day = 20,160 mmol/day
  • FENa  (excreted Na/ filtereed Na) = 0.5%
Notice how in this situation if we increase the sodium intake to better correlate with the typical American diet of 200 mmol/day of sodium per day the FENa increases to 1% without changing the volume status one bit. With stable renal function, FENa is a measure of sodium intake not volume status.

If this same patient now has a GFR of 20 mL/min and the same 100 mmol of sodium intake, the data looks like this:

  • Excreted sodium = daily sodium intake = 100 mmol/day
  • Filtered sodium = 0.02 L/min x 140 mmol/L x 1,440 min/day = 4,032 mmol/day
  • FENa  (excreted Na/ filtereed Na) = 2.4%
This situation is not an acute disease state. The patient has CKD, but stable renal function. They do not have acute tubular injury. They just have a decreased, but stable, GFR. The increase in FENa means that to get rid of the same sodium load, more of the filtered sodium needs to be excreted. This is what is happening in the undamaged tubules of intrinsic renal failure. The damaged tubules are shut down due to TG feedback. The undamaged tubules are dealing with the excess sodium load by reabsorbing less sodium, pushing up the FENa.

The FENa is not showing pathologically abnormal tubule response in the damaged tubules but actually showing a physiologically sound response to a decreased GFR from the intact tubules.

So who cares? Why does this matter?

It matters because this understanding allows one to understand why the FENa fails in certain circumstances. To me the three most important places the FENa fails are:
  • Acute tubular injury in a patient with burns
  • Acute tubular injury in a patient with CHF
  • Acute tubular injury in hepatorenal syndrome
In all three of these scenarios the patient will have a low FENa despite the acute tubular injury. The background clinical situation is one where the patient would naturally be very sodium avid. The ATI-damaged tubules are shut down and do not contribute to the urine. The intact tubules however are retaining sodium due to the volume depletion (burns), the heart failure, or the altered physiology of cirrhosis. The low FENa in these scenarios represents the overall sodium milieu and does not rise with the decreased GFR of from the acute tubular injury.

FENa: it's harder than you might think.

I have been called out for not including a reference to the classic article that I base al of my knowledge of AKI on, Acute Tubular Success. My bad. If you like reading stuff  like this, dont miss this classic.

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