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Monitoring therapeutic Dilantin in renal failure requires looking at the free not total Dilantin.

My fellowship director was the Great Brain, Dr Patrick Murray. Pat is quadruple boarded:

  1. internal medicine
  2. critical care
  3. nephrology 
  4. clinical pharmacology

Pretty intimidating. (If you have the time, check out his 179-slide presentation. Wow!)

One of the side effects of doing my fellowship under a professor in clinical pharmacology is that I learned more about drug monitoring in renal failure than any innocent nephrology fellow should.

One of the pearls he taught regarded the monitoring of therapeutic Dilatin (phenytoin) levels. the Renal Fellow Network discussed Dilantin pharmacokinetics twice but neither of the posts noted the change in protein binding that occurs with renal failure.

Dilantin is highly protein bound (90%) and only the free dilantin is therapeutically active. Uremia is associated with plasma molecules which displace Dilantin from albumin. This increases the active fraction of Dilantin, so sub-therapeutic total levels of Dilantin may represent appropriate free levels in the presence of renal failure.

I currently have a dialysis patient in the ICU who was seizing following a cardiac arrest. He was loaded with Dilantin and a few days later his labs showed:

Total phenytoin level of 5 mcg/mL, below the therapeutic target of 10-20. Simultaneously his free level was 1.14 mg/L. (Rant: How can the EMR express the total level as mcg/ml and the free level as mg/L. THEY ARE EQUIVALENT. Don’t hide it.)

So in this case the free dilantin is 23% of the total, rather than the normal 10%. Note that the total level appears sub-therapeutic but this patient would be poorly served by a re-loading of Dilantin as his free level is therapeutic.

Summary: in uremia always use the free dilantin level and don’t trust the total Dilantin level.

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Funniest thing a patient sent me

I just got this e-mail from a patient and felt compelled to share one short bit:

…i consider you a good friend and the
greatest doctor of all time (well, maybe
Dr. Frankenstein was a little better.  he
did after all assemble from corpse parts
a human entity and brought it to life.
trying topping that one Dr.Topf).

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ACEi, ARBs and Aldo Antagonists and the risk of Contrast Nephropathy

This is a question that comes up during almost every consult in patients with CKD about to receive contrast exposure. Should we stop ACEi and ARBs prior to exposure?

The data is confusing as summarized in the introduction to this latest analysis:

…Some studies have demonstrated that chronic medication with angiotensin-converting enzyme inhibitors (ACE-I) or AT-1 blockers was a risk factor for CIN [19,20], whereas other studies [21,22] found a protective effect in patients with CKD when exposed to CM.

If that doesn’t meet the definition of equipoise, I don’t know what does.

There still isn’t any prospective data but a recent reanalysis of a large (negative) trial on the use of hemodialysis to prevent contrast nephropathy attempts to answer the question.

When the baseline characteristics are separated by the presence of contrast nephropathy it reads like a rogues gallery of risk factors of contrast:

All of the following were significantly more frequent (or more extreme, i.e. greater age, higher Cr, more contrast, lower eGFR) in patients who developed contrast induced nephropathy:

  • Age
  • Diabetes
  • Insulin dependent
  • Creatinine
  • eGFR
  • Hemoglobin (that’s new)
  • RAAS blockade (ACEi, ARB, and aldo antagonist)
  • Loop diuretic
  • Contrast dose

The multivariate analysis showed RAAS blockade and hemoglobin to be independent predictors of contrast induced nephropathy:

The data is sure suggestive of an effect but given that both CKD and CHF are risk factors for contrast nephropathy and RAAS blockade is a first line therapy for both diseases I fear we could be looking at a classic bias by indication.
This is a question that is begging for an interventional trial. I’d let my patients be randomized to d/c ACEi/ARB versus no discontinuation. It sure would be better than another damn study on loop diuretics, mannitol and IV fluids 2009 (Hey AJKD! 1994 is on the phone and they say they’d like their study back).
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Plavix drug interaction

I know I’m a little late on this, but here is a sign we are using in our offices to alert patients to the problem with clopidogrel and omeprazole. Thought it might be useful for others.

Plavix Warning value=”http://d1.scribdassets.com/ScribdViewer.swf?document_id=24374327&access_key=key-2mnvhafk7m2nr8eu2ek9&page=1&version=1&viewMode=list”>            

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Contrast and residual renal function

In a previous entry I reviewed the iPhone app PubMedOnTap. I used this application to find articles regarding the question of whether iodinated radiocontrast media harms residual renal function for patients on dialysis. I came up with two “hits.”

The Palevski study is a retrospective analysis of PD patients with residual renal function who underwent coronary angiograms. They compared residual renal function after the angiogram to previous residual renal function. They also looked at mortality, change of modality and peritonitis. They created a control group composed of patients matched for time of initiation of PD, age, and diabetic status.

29 patients met the enrollment criteria. Residual renal function was assessed an average of 14.7 weeks following the procedure. 1 patient became permanently anuric following the angiogram.

The average loss of renal function for the cases was 0.09 ml/min/month versus 0.07 ml/min/month for the controls (p=0.53). Average decline in residual renal function for PD patients is said to be 0.1 mL/min/month.

5 patients had no residual renal function measured after the angiogram and a medical record review could not document why this happened. They were censored from the final analysis.

The Janousek study is a more rigorous design, as it is controlled. They did a matched cohort study of hemodialysis patients who underwent a endovascular procedures and matched them to similar patients who did not receive contrast.

All the participants had to have at least 500 mL of urine production per day.

The contrast patients received an average of 99 mL of iodixanol (isoosmolar contrast, Visipaque) with a range of 60-180 mL.

The authors specifically state that

Our aim was not to evaluate the immediate effect of contrast medium on residual renal function during the several days after application. Rather, we wanted to evaluate its long-term clinical effect. This is why we compared the volume of daily diuresis and RREC 3 months before and 3 months after ICA administration.

They found no difference in the rate of loss of residual renal function whether they measured it by urine volume (p=0.855) or creatinine clearance (p=0.573).

From the change in urine volume (the top chart), the value of a placebo group becomes clear. The contrast group does lose urine volume, but they lose it at roughly the same rate as the control group.
One of my concerns about the study is that since it was retrospective they purposefully restricted their analysis to patients who survived for the entire 6 month follow up period. From the Materials and Methods section:

Only clinically stable patients with no serious concomitant disease and who survived for a 6- month follow-up period with an unchanged dialysis strategy were evaluated.

So if contrast caused pre-mature death in dialysis patients, subjects having that outcome would not have been studied.

In the discussion the authors mention three other articles on the same subject:

They found two in NDT in addition to the pavlesky article. None showed a deleterious long term effect of contrast.

  • The first was a prospective trial by Dittrich el at. of 10 peritoneal dialysis patients with 8 patients as controls. They found a temporary drop in residual renal function that was erased after 30 days.

  • The second was a prospective cohort trial by Morrane et al. of 72 peritoneal dialysis patients, half of which were exposed to contrast. After two weeks there was no difference between the two groups or from baseline figures in regards to CrCl, urine volume or residual renal function.

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How to make a cool clinic diagnosis

I had a great case yesterday in clinic.

The patient was a 55 year old woman with HIV and a chief complaint of gradually climbing creatinine. Among her medications were Truvada and Norvir.

Truvada is one of three brand name drugs that contains tenofovir:

  1. Viread: tenofovir
  2. Truvada: emtricitabine-tenofovir
  3. Atripla: efavirenz-emtricitabine-tenofovir
Tenofovir rarely causes renal failure through proximal tubule toxicity. One of its hallmarks is a Fanconi syndrome, though the renal failure can occur without Fanconi’s. Fanconi’ syndrome is generalized dysfunction of the proximal tubule, so metabolites normally reabsorbed in the proximal tubule are wasted in the urine. Patients have amino aciduria, bicarbonaturia (RTA type II), inappropriate phosphaturia and glucosuria. Because of the increased phosphaturia, hypophosphatemia is a surprisingly sensitive indicator of tenofovir toxicity (20/20 cases).
This patient’s creatinine rose from 1.4 in March of ’09 to 1.7 in November. The primary care doctor that handles this patient’s HIV had checked an ultrasound (9 and 10 cm kidneys), and albuminuria (400 mcg/min).
Here are the results of his U/A we did in the clinic:
I focused on the glucosuria and concluded that if her blood sugars are normal then she must have proximal tubular dysfunction and likely tenofovir toxicity.
Her blood sugar was 87. The Tm for glucose is roughly 200, so a serum glucose of 87 should not cause any glucosuria.
The Truvada was stopped. The patient is also on ritonovir (Norvir). Ritonovir is found in 72% of patients with tonofovir induced Fanconi’s syndrome, so it maybe an important co-factor in the development of this condition. We did not stop the Norvir, should we?

 I will follow up with the patient in the month. Hopefully she will do well.

Here is a talk I gave on HIV and the Kidney: