When to adjust the dose for patients having renal failure?

Let me give you an example, using some actual laboratory values. In this patient, the serum creatinine value was 1.04, and the eGFR, which in this case was calculated using the MDRD equation for a non African-American male was 76. This patient weighed 69.5 kilograms, was 63 years old at a body surface area 1.85 meters squared. And the patient’s Cystatin C was 0.74. What we find is that the Cockcroft-Gault estimate using the Cockcroft-Gault equation was 71 milliliters per minute. Now, this can be converted to an adjusted based on 1.73 meters squared value of 66 milliliters per minute. Note that because the patient’s body surface area was greater than o1.73 meters squared, the adjusted value is less than the unadjusted value.

The MDRD value as shown in the laboratory report at the top of the slide was 76 ml/min per 1.73 meters squared. CKD-EPI using serum creatinine only would be 80 milliliters per minute for 1.73 meters squared, and CKD-EPI using both serum creatinine and Cystatin C would be 93 ml per minute for 1.73 meters squared. So, note that there’s a difference in terms of whether the result is adjusted to body size or as the Cockcroft-Gault equation, we had to go the additional step to calculate the corrected value and consider also that the Cockcroft-Gault equation is a correcting clearance estimate whereas the MDRD and the CKD-EPI is a GFR estimate.

So there are some differences, and when renal dosing guidelines are based on a Cockcroft-Gault equation from those studies were using a Cockcroft-Gault equation, it can be very misleading and perhaps inappropriate to use a patient’s MDRD estimate of GFR when the dosing guidelines were based on Cockcroft-Gault. Let’s summarize the impact of obesity serum creatinine and creatinine clearance using this table. We’ll go one by one looking at each monitoring parameter and identify whether the result would be impacted by obesity. First of all, the serum creatinine would not be affected by obesity, because obesity doesn’t have anything to do with whether the patient has normal muscle mass. Therefore, the impact on renal assessment would be none.

The creatinine clearance as estimated by the Cockcroft-Gault equation as we indicated. If the actual body weight is used, it would be high. And if the ideal body weight is used, it would be low. So there would be an over estimate of creatinine clearance using actual body weight, and under estimate using ideal body weight. That’s why many clinicians choose to use an adjusted body weight that kind of fudges the answer between the two using that 40% adjustment factor. Creatinine clearance as estimated by MDRD or CKD-EPI, there’s no significant effect based on obesity. And therefore, the impact and renal assessment there would be none, and 24-hour urine collection is not affected because it’s an actual urinary excretion measurement of serum creatinine.

Actually, we have creatinine clearance. Therefore, there would be no impact on renal assessment. The primary error from a 24-hour urine collection, which can be significant is missing some of the urine that’s actually produced during based just simply on collection error. If we compare now those same parameters using situation in which a patient has low muscle mass, the impact on serum creatinine or granting clearance, the result on serum creatinine is that it will be lower than expected, lower than it should be based on the patient’s renal function, due to decreased creatinine production or the patient has low muscle mass. And therefore, this would be an overestimate of the patients renal function.

The creatinine clearance estimation from Cockcroft-Gault would be falsely high because we’d be putting a falsely low serum creatinine into the denominator of that equation. This would also overestimate our determination of the patient’s renal function. Creatinine clearance by MDRD or CKD-EPI, this would be falsely high for the same reasons as Cockcroft-Gault. These have the serum creatinine in the equation and if serum creatinine is falsely low due to low creatinine production, it will impact the results from the MDRD or CKD-EPI, which would overestimate the patient’s renal function. And the creatinine clearance based on 24-hour urine collection, again, would not be affected because it’s a true measurement of urinary excretion of creatinine.

And the only error that we’d be concerned about there would be an incomplete urine collection. This chart identifies drugs that are typically affected by renal function. Such that there may be a dose adjustment warranted. The drugs on the left have a very high degree of urinary excretion. More than 90% of these drugs are excreted unchanged in the urine. The other drugs on the right-hand column are also have significant renal excretion. To the extent that dosing adjustments generally need to be made when a patient has some degree of renal impairment. You’ll notice that a lot of these drugs are antibiotics. So it’s fairly common for antibiotics to require dose adjustments when the patient has renal impairment.

By the way, when we’re identifying whether or not there’s a potential risk, and whether there may be a need to adjust the patient’s dosing regimen due to renal impairment, two factors that should be considered are the FE, the fraction excreted, unchanged in the urine. If that is greater than 0.3 meaning that more than 30% of the elimination of the drug from the blood is based on urinary excretion of unchanged drug or unmetabolized drug. That’s an indication that the renal, the extent of renal excretion is enough that renal impairment might be a problem. And the measurement of renal function whether it’s based on GFR creatinine clearance, and that is less than 60 milliliters per minute.

That’s an indication that the patient’s renal function may be impaired enough, that there may be a need for dosing adjustment. Let’s review renal function. And then we’ll see if you can answer a question about it. First of all, for obese patients, the creatinine clearance estimation from the Cockcroft-Gault equation based on actual body weight will be high or low ? The answer is high. For obese patients, the Cockcroft-Gault estimation of creatinine clearance based on ideal body weight will be high or low ? The answer is low. For cachectic patients, the Cockcroft-Gault estimate of creatinine clearance will be is it high, low or unaffected? The answer is high.

Remember, for cachectic patients, the serum creatinine is going to be low, but the estimate of creatinine clearance, because serum creatinine is inversely proportional to creatinine clearance will be high. For cachectic patients, the urine collection method of crediting clearance will be unaffected for cachectic patients even though the creatinine production is low based on low muscle mass. We’re actually measuring creatinine excretion, and so low production does not interfere with the urine collection method since it’s a true excretion determination. If you use the Cockcroft-Gault equation to estimate creatinine clearance and the patient has a BSA of 3.2, significantly larger than the standard 1.73 that’s used, will the corrected creatinine clearance be larger or smaller than the patient’s actual creatinine clearance?

The answer is smaller. Because the patient’s body surface area is much larger. so when it’s adjusted and you multiply the actual value by 1.73 meters squared over 3.2 meters squared, the result will be smaller. What are the two major differences between the results of the Cockcroft-Gault equation and the MDRD or the CKD-EPI ? That refers to the fact that CKD-EPI and the MDRD provide a measurement of GFR, whereas the Cockcroft-Gault is a measurement of creatinine clearance, And the CKD-EPI and the MDRD provide a corrected value to 1.73 meters squared, the Cockcroft-Gault equation is incorrect.

A drug is considered to be really excreted if the FE is less than what value, excuse me, greater than 0.3, greater than 30% of the drug is excreted unchanged in the urine. And lastly, our dose adjustment might be needed if the patient’s GFR is less than 60 milliliters per minute.