Cardiorenal Syndrome. Revised

I gave the cardiology fellows at St John Hospital and Medical Center a lecture on cardiorenal syndrome this morning. I revised and expanded the lecture I used for the residents:

It could still use a slide or two on the various loop diuretics and their uses.

We also had an interesting discussion on the data suggesting that loop diuretics maybe harmful in acute decompensated heart failure. I should include a couple of slides on that.

Overall a significant upgrade. You can find the lecture in the usual place.

Cardiorenal syndrome

Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the authorOn 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.

second lecture of the year: acute kidney injury

This is a significant upgrade from the version I posted a couple of years ago. I put the lecture together right before the ATN trial was published. I finally got around to updating the presentation to include that data. I also updated the NGAL section and added some data on avoiding volume overload.

I used a number of the posts on the blog to allow me to rapidly update the presentation. I was pleased with how well my ATN commentary/review stood up.

Volume, a new target for dialysis and acute renal failure?

One of the major advancements in nephrology in the first decade of the 21ast century was the rejection of Kt/V as a treatment target in dialysis. In a field that is lacking in randomized clinical trials we had three well done randomized clinical trials designed to verify the mounds of observational data. In all three Kt/V as an expression of dose failed.

Chronic hemodialysis: HEMO

  • eKt/V of 1.05 vs 1.45 (or a spKt/V of 1.2 vs 1.6) 

Peritoneal dialysis: ADEMEX

  • Increase in PD dose such that they move from less than 40% at Kt/V of 2.0 to 83% at Kt/V of 2.0

Dialytic support for acute renal failure: VA/NIH ATN trial

  • 3 days a week dialysis versus 6 days a week all at a single-pool Kt/V of 1.2 to 1.4 per session
  • Hemodynamicly unstable patients were randomized to one of two levels of CVVH 20 or 35 ml/kg/hour of total CRT effluent
All three looked at variations on Kt/V tuned to the individual clinical scenario. Varying Kt/V in each of these clinical scanrio made not a whif of difference to the patients.

In the aftermath of such intellectual carnage nephrology is desperately seeking a replacement. My experience with nocturnal dialysis and the amazing work coming out of Canada makes home hemo look like the most appealing option. Getting results comparable to transplant makes it look like an entirely new modality compared to traditional in-center hemo.
One of the aspects that made Kt/V so appealing was how it was a useful in any situation involving dialysis. (The lessons from NCDS study on chronic in-center hemodialysis guided the definition of adequate dialysis for ARF in the ATN trial)

What lessons does home hemo have to teach acute renal failure in the ICU? What lessons does it have for peritoneal dialysis. One could argue that one of the central problems in modern dialysis is fluid management. Too many of my patients are chronically fluid overloaded leading to hypertension and over worked hearts. Home hemo corrects hypertension. Is solving that cardiovascular problem accounting for much of the improved clinical outcomes?

If that is the case, then there is a clear lesson that we can take from home hemo and apply to the ICU. 
Don’t let your patients get volume overloaded
We covered this in journal club last thursday: Fluid Overload and Mortality in Children Receiving Continuous Renal Replacement Therapy

The study is a retrospective interpretation of registry data on children with acute renal failure receiving continuous renal replacement therapy. Each patient was given a fluid overload score by calculating a percentage overload:

They divided patients into three strata:

  1. <10% overload
  2. 10-20% overload
  3. ≥20% overload
They also used percentage overload as a continuous variable for the primary multivariate analysis.
The primary data is shown in table 2.
It should be immediatly obvious that the patients with more volume overload were sicker, they had signifigantly:
  • longer ICU stay
  • higher mortality
  • more multi-organ dysfunction
  • more likely to be intubated
  • more inotropes
  • more sepsis
  • higher PRISM score
For that reason I am not going to spend time discussing the univariate analysis and go straight to the multivariate analysis:

Worse fluid overload severity remained independently associated with mortality (OR, 1.03; 95% CI, 1.01-1.05). The relationship was satisfactorily linear and the OR suggests a 3% increase in mortality for each 1% increase in degree of fluid overload at CRRT initiation.

That is impressive. If the results hold up and aplies to adults it should scare the crap out of anyone who regularly rounds in the ICU. Think of a typical 80 kg adult who has total input of 2,400 mL (100 mL/hr) and has 1,600 mL of urine output, 67 mL/hour. That is a positive balance of 800 mL or 1% of body weight. If that goes on for 3 days and then the patient becomes oliguric with only 400 mL of urine output for two days (2,000 mL positive per day) before initiating CRT. That patient would be up 6,400 mL or 8% of bodyweight: Those relatively innocuous seeming numbers would represent a 24% increase in mortality compared to someone with matched ins and outs. Yowsa!
This is an observational study and it is important not to accept he results as truth but it is certainly a suggestive lead.

lowest FeNa I have ever seen

I was consulted on a patient with autoimmune hepatitis and acute kidney injury. The patient has ascites and was admitted with a small bowel obstruction.

I’m not sure if it is actually the lowest but it is remarkably low:

serum Na 147 mmol/L
serum Creatinine 1.77 mg/dL

urine Na <10
urine Cr 148

I assumed a urine sodium of 5 mmol/L

FENa= 0.04%

This is 4 molecules of sodium excreted for every 10,000 filtered. Amazing.

Cast Nephropathy and plasmapheresis

Does removal of the light chains with plasmapharesis reduce the severity of cast nephropathy? We know that renal failure is a terrible prognostic factor in multiple myeloma so fixing acute renal failure is important.

Renal failure comes in many different flavors with myeloma:

  • Light chain deposition disease
  • Heavy chain deposition disease that I have never seen but Steve Rankin had a case as a fellow.
  • Amylloidosis
  • Hypercalcemia
  • Cast nephropathy
Only the last is amenable to plasmapheresis. Whether it works has been the subject of three prospective randomized studies:

  1. Zucchelli 1988
  2. Johnson 1990
  3. Clark  2005 (PDF)

Though not randomized this recent article from KI should be of interest (Thanks Kyste):

Leung et al. Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int (2008) vol. 73 (11) pp. 1282-8.

How do you go from an EGD to acute kidney injury?

We had an interesting consult a few weeks ago.

The patient was an elderly gentleman who recently underwent an EGD for gastritis-like symptoms. A few days after the procedure he received a call from his gastroenterologist telling him that he had H. Pylori and needed to start an antibiotic. He was prescribed PrevPac for 10 days. He almost immediately began to feel worse. His wife ultimately stopped giving him the PrevPack after about four days of increasing weakness, lethergy and nausea. Despite stopping the new medicine the patient continued to deteriorate. He was admitted about 2 weeks after the EGD.

His creatinine had risen from a baseline of 1.2 mg/dL to 4.5 mg/dL. Our initial thought was that he was pre-renal. We prescribed 0.9% saline but the patient didn’t respond, and his creatine continued to rise.

One clinical pearl that I repeatedly teach fellows is not to under treat pre-renal azotemia. If you think the patient is volume depleted give enough fluid that the next day if the creatinine has not improved you will be convinced that the patient is no longer volume depleted. You want to fully rule-out volume depletion after the first day.

This patient didn’t respond to fluids so we reevaluated the history. PrevPac, what’s in that?

  • Lansoprazole
  • Amoxicillin
  • Clarithromycin
Clarithromycin is a potent inhibitor of CYP3A4 so it interacts with a lot of medications. Our patient was on simvastatin. Let’s check out what does Dr. Google has to say about that:
We check his CPK and its 8,000 almost a week after he stopped taking the Clarithro.

Rhabdo induced acute kidney injury due to a drug interaction.

Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Clarithromycin is a potent inhibitor of CYP3A4, the major enzyme responsible for simvastatin metabolism.

Effects of Clarithromycin on the Pharmacokinetics of SimvastatinCompared with simvastatin alone, coadministration of clarythromycin and simvastatin significantly increased the peak concentration and the area under the curve for simvastatin by approximately 8-fold (p<0.0001). Levels of simvastatin acid were also significantly (about 14-fold) higher during clarythromycin treatment compared with simvastatin alone (p<0.0001).

If the figures on pharmacokinetics from that last article are to be believed then 500 mg of clarithromycin magnifies 80 mg of daily simvastatin to an equivalent daily dose of 640 to 1,120 mg.

Rhabdomyolysis induces acute kidney injury from myoglobin. Myoglobin can precipitate in the presence of acidic urine. The heme component of myoglobin can generate free-radicals which can damage lipid membranes. Patients develop vasoconstriction in response to rhabdomyolysis, both from the direct effect of the myoglobin on the renal vasculature and due to the movement of intravascular fluid into the damaged muscles. This gives a pre-renal picture on the fractional excretion of sodium.

Evaluating volume status can be tricky because patients will often have peripheral edema from the inflammation associated with the rhabdomyolysis. Additionally the BUN:Cr will often be low as the creatinine tends to rise quicker in rhabdomyolysis than in other forms of renal failure. This is usually explained by the release of intramuscular creatinine rather than just a failure to clear creatinine. The younger age and increased frequency of men suffering from rhabdomyolysis may also play a role in this observation.

The electrolyte abnormalities of rhabdomyolysis:

  • Hyperkalemia
  • Hyperphosphatemia
  • Hypocalcemia (early)
  • Hypercalcemia (late)
  • Hyperuricemia
  • Anion gap metabolic acidosis

 The NEJM recently did a nice review of rhabdomyolysis which presents the recent inconclusive data on alkalinization (not proven to be helpful but the animal/disease models make it look like the right thing to do), mannitol and diuretics and use of high flux dialyzers.

The Annals of Internal Medicine recently published a review of Statin-Related Myopathy. Here is what they had to say about drug interactions:

Because simvastatin, lovastatin, and atorvastatin are primarily metabolized through the cytochrome P450 3A4 (CYP3A4) isoenzyme (43), inhibitors of CYP3A4 could theoretically increase serum statin levels and exposure to susceptible tissues. Drugs known to interact with statins include protease inhibitors, cyclosporine, amiodarone, and fibrates (44, 45). Protease inhibitors are potent CYP3A4 inhibitors and thus can increase up to 30 times the plasma concentrations of certain statins (45, 46). Consequently, both simvastatin and lovastatin should be avoided in pa- tients receiving protease inhibitors (42, 45, 47). Cyclosporine is a potent inhibitor of not only CYP3A4 but also several membrane transporters, and it increases the phar- macokinetic area under the curve of statins by 2- to 25- fold, with many reported cases of rhabdomyolysis (44). Statin dosages in patients receiving cyclosporine have therefore been limited to 5 mg/d for rosuvastatin, 10 mg/d for simvastatin and atorvastatin, and 20 mg/d for lovastatin (42, 47–49).

Pravastatin is not metabolized by the P450 system but is excreted renaly. Fluvastatin and rosuvastatin are metabolized by an alternative enzyme, CYP2C9.