by Elmer M. Cranton, M.D and James P. Frackelton, M.D.
ABSTRACT: Twenty-four hour urinary creatinine clearance measurements on
ambulatory patients are not reliable. Collection errors are common as
outpatients. Serial measurements of serum creatinine and routine urine analyses
are more reliable to monitor for renal safety during a course of EDTA chelation
therapy. Intravenous EDTA chelation therapy can cause renal impairment, if not
properly monitored. An occasional patient will unpredictably be susceptible to
transient EDTA nephrotoxicity. Serum creatinine levels, carefully monitored
throughout therapy, will safeguard renal function, and are essential if
infusions are given more often than twice weekly or when kidney function is
impaired at the outset. The Cockcroft-Gault equation accurately reflects
glomerular filtration rate and provides an accurate, computed creatinine
clearance estimate. That formula and has been modified, based on blood level
measurements of EDTA during therapy, to provide approximately the same blood
levels of EDTA in all patients.
Serum Creatinine and Creatinine Clearance
Twenty-four hour collection of urine specimens for creatinine clearance measurement is not reliable in ambulatory patients, especially the elderly and infirm who are commonly treated with EDTA chelation therapy.1-3 Rates of glomerular filtration (approximated as measured creatinine clearance) can more accurately be assessed by measuring serum creatinine alone, and then computing clearance. Serum creatinine levels can thus be used to accurately compute glomerular filtration rate.2,3 The dosing protocol below is designed to provide approximately the same blood levels of EDTA throughout the infusion for all patients, regardless of age, sex, weight or kidney function.
COCKCROFT-GAULT EQUATION, MODIFIED
CrCl = (140 — Age) X (LBW X 1.33)
(72 X Cr)
This can be formula simplified as follows:
CrCl = (140 — Age) X LBW
54 X Cr
CrCl = computed renal glomerular filtration rate in ml/min
Age = patient’s age
LBW = computed lean body weight in Kg, see below.
Cr = serum creatinine in mg/dL
For women, multiply the above result by 0.85
EDTA DOSE TO BE ADMINISTERED IN EACH INFUSION IS COMPUTED AS
(TO BE ADMINISTERED SLOWLY, NOT LESS THAN THREE HOURS)
50 mg EDTA per (Kg LBW X 1.33) X (CrCl/100)
The maximum dose is usually 3.0 grams, unless otherwise
individualized a physician
Correct for CrCl/100 only if creatinine clearance
is less than 100 ml/min.
Maximum rate of infusion is 16.6 mg/min X CrCl/100, for a 70 Kg patient
LEAN BODY WEIGHT (LBW) IN KG AS USED IN ABOVE COMPUTATIONS
Lean body weight for males is computed at 50 kg plus 2.3 kg for each inch of height over 5 feet.
Lean body weight for females is computed at 45.5 kg plus 2.3 kg for every inch of height over 5 feet.
Actual weight is used whenever actual weight is less than computed lean body weight.
As reported by Dr Reidenberg at Cornell Medical School in the New England Journal of Medicine, "Creatinine . . . formation decreases with age. . . Elderly people can have markedly decreased renal function without having serum creatinine levels above the upper limit of normal. . . In patients with stable renal function, who are not massively obese, or edematous . . . we have found the Cockcroft-Gault equation accurate.”3
EDTA is distributed in extracellular fluid. It is not fat soluble and does not significantly enter cells. The safe dose of 50 mg/kg of body weight was originally derived on an average population with approximately 25% of their body weight as fat. To prevent obese patents from receiving an overdose, the administered dose of 50 mg/kg is computed above using lean body weight plus 33 percent, which produces the equivalent of 25 percent body fat. Similarly, the Cockcroft-Gault formula was found to be inaccurate for obese patients. Cockcroft and Gault derived their formula using average Americans who had approximately 25% of their body weights as fat. By using 1.33 times LBW to compute renal clearance using the Cockcroft-Gault equation, that source of error is also minimized. In the original ACAM Protocol, that correction for body fat was inadvertently omitted, causing inappropriately reduced doses in smaller patients.
Derivation of the above protocol is somewhat counter-intuitive, since weight seems to enter into the computation more than once. Weight is actually used three times, but is canceled out in the Cockcroft-Gault computation. The 72 constant in the denominator actually represents kg and produces a correction factor to adjust for the weight of a patient who weighs more or less than that amount. Without that adjustment, the final computation would only be accurate for a person who weighs 72 kg. By limiting weight of obese patients to 1.33 times LBW when computing creatinine clearance, we prevent erroneously high computations for obese patients
Most medicines enter into cellular metabolism and remain active for many hours. EDTA is different and unique in the following ways:
1) EDTA is inert and leaves the body unaltered. It does not react or interact chemically with metabolism, other than to bind, redistribute or remove loosely attached, polyvalent, cationic metal ions in the urine.
2) EDTA has a very short half-life in the body with normal renal function, approximately 42 minutes, and is passed out in the urine unchanged in a very short time.
3) EDTA distribution in the body is solely extracellular. Because EDTA is not fat-soluble and does not cross cell membranes, its distribution is restricted to plasma and extracellular fluid (ECF)—approximately 8 to 10 liters in volume.
4) Although EDTA remains outside of cells, much of its beneficial effect relates to removal, redistribution and balancing of metal ions within cells. Benefit will therefore be enhanced by maintaining a concentration in plasma and ECF adequate to produce a high diffusion gradient across cell membranes lasting several hours.
5) Disodium EDTA infusion causes a temporary lowering of plasma calcium concentration, which causes a pulsitile increase in parathyroid hormone. This sequence of events is thought to be partially responsible for long term benefit. However, if the computed dose of disodium EDTA is infused too rapidly, plasma calcium drops too low, causing undesirable side effects. Decades of experience tell us that by slowly infusing the dose of disodium EDTA computed using the formula above, optimal benefits an be achieved with minimal side effects.
Extracellular fluid exists largely in lean tissues. Adipose tissue has very little water or blood flow. The protocol dose of EDTA for patients with normal renal function is 50 mg EDTA per kg of LBW X 1.33, infused over 3 hours. That dose has been found by experience to be the maximum safe dose for patients with normal kidney function. When kidney function is normal (creatinine clearance 100 or higher), no further adjustment is made.
When renal clearance is reduced, the fact that EDTA is otherwise lost in urine at a very rapid rate during the 3-hour infusion becomes an important variable. This is best understood by visualizing a large container of plasma (extracellular fluid). That plasma is continuously being pumped through a filter (kidneys) that totally removes EDTA from approximately 130 ml per minute of solution. That represents the normal rate of glomerular filtration (creatinine clearance) in a young, healthy male of average weight. At that rate, 50-percent of a bolus dose of the EDTA would be removed in 45 minutes, 75-percent in two hours, and so forth. The goal of chelation therapy is to bathe cells of the body with a therapeutic concentration of EDTA for three hours or longer. That is achieved by continuously infusing EDTA at a constant, safe rate over 3 hours, to compensate for rapid loss in urine during that time. Decades of experience tell us that a dose of 50 mg of EDTA per kg body weight, infused over 3 hours, provides optimum benefit, and is safe when given at a maximum infusion rate of 16.6 mg/min in an adult of average weight and normal kidney function.
In a large series of patients with varied kidney function and body weight, plasma EDTA levels were measured 45 minutes after beginning each infusion (one half-life) and again at 3 hours, at the end of each infusion. By adjusting the dose of EDTA using the formula above, it was documented that equivalent plasma levels of EDTA were measured in all patients.(7)
Total volume of extra cellular fluid is directly proportional lean body weight. Assume, for example, that the volume of plasma and extracellular fluid is 9 liters in a average, elderly 72 Kg patient. Assuming that EDTA would be totally removed from 6 liters of blood per hour, at a filtration rate of rate of approximately 100 ml/min, EDTA would be removed from 4.5 liters of plasma every 45 minutes. The half-life in blood of EDTA would therefore be 45 minutes. That corresponds exactly to the observed half-life as reported in the scientific literature. The EDTA initially infused has been largely eliminated by 90 minutes, half way though a 3-hour infusion, in an adult patient of average weight with reasonably healthy kidneys. The blood level is continuously replenished by infusing EDTA at a rate of 16.6 mg/min throughout the infusion. If kidneys are impaired and renal clearance is reduced to 50 ml/min, for example,--as often occurs in chronically ill elderly patients--EDTA would be cleared from only 3 liters of plasma per hour. In such a patient, with creatinine clearance reduced to 50 ml.min, it is therefore necessary to reduce the dose-rate of infusion by half to achieve approximately the same blood level during that same period of time. If the blood level becomes excessive, EDTA in the renal filtrate becomes excessive, potentially causing renal tubular cells to swell. This can lead to further renal impairment.
Cockcroft and Gault, who derived the original equation, found that it gives a correlation coefficient between computed and actual measured creatinine clearance of 0.83.2 The Cockcroft-Gault equation was found to overestimate renal function in very obese or edematous patients and in patients with rapidly deteriorating kidney function. It is possible, however, to correct at least partially for such overestimates by limiting weight in the computation to 1.33 times LBW.2,3
Although rare, there are well documented instances of patients suffering serious renal impairment as a result of intravenous EDTA. Careful monitoring of serum creatinine is therefore essential to insure safety during therapy. Technology has progressed to the point where rapid and accurate creatinine determinations can be performed inexpensively in a physician's office. Serum creatinine can be measured quickly and easily using the Refletron®, or a similar dry-reagent laboratory instrument. Accurate results may be obtained within a few minutes and can conveniently be done prior to a chelation infusion, if kidney function is in doubt. If dry-reagent chemistry is not used, lipemic serum must first be ultracentrifuged to clear chylomicrons, which will otherwise cause erroneous measurements.
Safety of EDTA
Intravenous EDTA, properly administered, is relatively safe in comparison to most other prescription drugs.4,5 It is unjustified, however, to state that EDTA is not potentially nephrotoxic. Nephrotoxicity remains a risk for some patients; primarily the elderly with preexisting impairment of renal function.4-6 Serum creatinine levels should be carefully monitored throughout a course of chelation therapy. If a longer time is allowed between infusions, and if the dose-rate of EDTA is reduced to a safe level compatible with renal function, using the above protocol, most patients can safely benefit from a series of EDTA infusions, despite mild to moderate pre-existing renal impairment-—up to a serum creatinine level of 3.0 mg/dL if great care is used. Continued treatment in the face of rising creatinine levels, however, can result in progressive renal impairment and, in rare instances, has lead to temporary renal dialysis.
In one published report, a patient required renal dialysis to prevent death from EDTA chelation therapy.6 That same patient was later reported to be recovered with marked improvement of symptoms of atherosclerosis for which chelation therapy was administered. Renal function eventually returned to a state better than existed prior to administration of EDTA.
If chelation therapy is temporarily withheld in the face of a progressive rise in serum creatinine, kidney function can be expected to slowly return to baseline levels--and not uncommonly to an even more favorable level, reflecting improvement from therapy. McDonagh and associates reported that in a series of 383 chelation patients, six had pre-existing elevations of serum creatinine at the beginning of therapy. Infusions of EDTA were given approximately once each week. One of the six patients who began therapy with an elevated serum creatinine experienced relatively rapid deterioration in kidney function shortly after therapy was begun (this occurred even though treatments were given only once each week). Serum creatinine doubled after only a few infusions.5 Therapy was then discontinued and serum creatinine slowly returned over three months to a level that was even closer to normal than before therapy.
If serum creatinine had not been closely monitored during therapy, that patient might have suffered far more serious renal impairment. It is not uncommon for elderly patients and those with atherosclerosis to have mild to moderate impairment of renal function at the onset of EDTA chelation therapy. Most such patients tolerate chelation without difficulty if closely monitored. An occasional patient, however, will be unpredictably sensitive to EDTA and will show a transient deterioration of serum creatinine, sometimes after only a few infusions. It is not possible to predict in advance which patients will be unduly sensitive to EDTA and which will tolerate the infusions without difficulty. Only by serially measuring serum creatinine can potential renal complications be avoided. Patients with renal impairment and elevated serum creatinine should have serum creatinine measured at the time of every EDTA infusion.
Patients who are found less tolerant to EDTA should wait longer between infusions, often two weeks or more. In addition, it may be necessary to administer a lower dose and with a reduced infusion rate of four or more hours.
References1. Payne RB. Creatinine clearance: A redundant clinical investigation. Ann Clin Biochem. 1986;23:243-250. 2. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.
Copyright © 2012 Elmer M. Cranton, M.D., all rights reserved