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.

Statins fail again

Statins have a tortured relationship with nephrology. Our patients have accelerated atherosclerosis and they die overwhelmingly of cardiovascular disease. So one of my primary jobs is to continually optimize cardiovascular risk factors to save my patients

Control blood pressure, start an aspirin, and maximize the statin are the lather, rinse, repeat of my world.

That said we have little data that this makes a whit of difference, at least in our dialysis patients.


  • No randomized trials have been done on the role of aspirin to prevent cardiovascular events among dialysis patients.
  • Aspirin was found to increase acute coronary syndrome in an unbadjusted analysis but was not significant in multivariate analysis.
  • Berger et al. (PDF), however found a dramatic reduction in 30-day mortality for patients with acute myocardial infarction given aspirin. Unfortunatly fewer dialysis patients received ASA and other standards of heart-attack care (beta-blocker and ACEi) than patients not on dialysis.
The survival of patients based on whether they received ASA for their acute MIThe use of standard therapies for acute myocardial infarction was lower among dialysis patients, even patients deemed ideal candidates for the therapy.

Blood pressure

  • Hypertension, along with cholesterol and obesity, is subject to reverse epidemiology in dialysis patients. This means that observed epidemiology trends are the opposite of what you would expect from data on non-dialysis patients. Lower blood pressure leads to high mortality, lower cholesterol leads to higher mortality, increased BMI yields better observed survival. The observational data, however, does not mean that interventions to lower blood pressure will lead to the same bad outcomes.
  • A recent meta-analysis (PDF) of 8 randomized trials of anti-hypertensive therapy gives credence to the practice of treating hypertension in dialysis patients.

  • One thing high lighted by the trial, though, is the paucity of evidence for this treatment: They were able to find only 1,679 patients. Terrible.


  • The 4D study is one of the few randomized controlled trials in dialysis patients and unfortunately did not show any improvement in mortality with atorvastatin. The study randomized 1,255 hemodialysis patients to either 20 mg of atorvastatin or placebo. After 4 years they found the statin was safe and effective in reducing the median serum LDL cholesterol level by 42%. However, the primary endpoint—cardiac death, nonfatal MI, and stroke—was reduced by insignificant 8% (P=0.37).

  • The authors found a significant increase in fatal strokes among the patients randomized to atorvastatin. (RR 2.03, P=0.04).
  • Today came word that another randomized controlled trial on statins among hemodialysis patients, AURORA, was also a bust. Published yesterday in The Journal, AURORA randomized 2,776 dialysis patients to 10 mg of rosuvastatin (Crestor) or matching placebo. The end-point was a composite of CV death, non-fatal MI, and non-fatal stroke. Average follow-up was 3.8 years and there was no difference in the primary outcome (396 outcomes with rosuvastatin versus 408 on placebo, P=0.51).

  • AURORA found no increased risk of strokes as found in the 4D study.