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Use of the Friedewald formula to estimate LDL-cholesterol in patients with chronic renal failure on dialysis.

Increased plasma cholesterol, particularly that portion associated with LDL, is an established risk factor for coronary heart disease [1, 2]. As a consequence, it is widely recommended [3] that LDL-cholesterol be determined in individuals with increased total cholesterol. Because isolation of the LDL fraction requires ultracentrifugation, a technique not generally available in service laboratories, the concentration of LDL-cholesterol is usually calculated by the formula of Friedewald et al. [4].

The Friedewald formula provides an adequate estimate of LDL-cholesterol for most fasting specimens but is known to be less reliable as triglyceride concentration increases [5]. Moreover, in patients with chronic renal failure, in whom an accumulation of remnant particles and increased concentrations of IDL-cholesterol have been found [6, 7], the estimate is possibly further compromised [8].

Here we report results on specimens obtained from patients on dialysis with chronic renal failure that show no greater disparity between measured and estimated LDL-cholesterol concentrations than those seen in other patient groups in which the Friedewald formula is frequently used. Additionally we have reexamined the effect of IDL and VLDL composition on the reliability of estimations made with the formula.

Two sets of blood specimens taken 6 months apart were obtained from 106 patients receiving hemodialysis or continual ambulatory peritoneal dialysis [9]. Within this 6-month period, some patients received an inhibitor of hydroxymethylglutaryl-CoA reductase, some an inhibitor of angiotensin-converting enzyme, some both treatments, and some placebo only. Blood collected after an overnight fast and separated within 4 h provided serum specimens for analysis.

Total cholesterol and triglyceride were assayed enzymically with reagents from Boehringer Mannheim. HDLcholesterol was assayed after precipitation of the apo B-containing lipoproteins with phosphotungstate and magnesium ions [10]. The performance of these assays was regularly certified by reference to samples provided by the Centers for Disease Control and Prevention, Atlanta, GA. Ultracentrifugation was carried out as described by others [11] for 15 h at 120 OOOg with a TFT 80.4 fixed-angle rotor in a Centrikon T-2070 centrifuge (Kontron Instruments). Cholesterol and triglyceride contents of supernatant fractions obtained after the tubes were sliced [11] were measured; the fraction floating at a relative density (d) of 1.006 was taken to represent VLDL and that floating at d 1.019 obtained by adjustment of 20 volumes of serum with 1 volume of NaBr solution (d = 1.27, -3.9 mol/L) was taken to represent VLDL plus IDL. The contents of IDL alone were calculated by subtraction. When in other experiments this technique was extended to permit sequential isolation of LDL and of HDL [11], the mean recovery of total cholesterol was 90% (range 8695%) and of triglyceride was 92% (range 88-95%).

LDL-cholesterol was calculated as total cholesterol - HDL-cholesterol - VLDL-cholesterol; VLDL-cholesterol was either measured directly (after ultracentrifugation) or calculated as 0.456 X total triglyceride concentration expressed in mmol/L (Friedewald).

Analysis of 204 specimens with complete data from the 106 patients showed concentrations (mmol/L) of total cholesterol of 3.16-9.25 (median 6.00), triglyceride of 0.48-7.74 (median 2.01), VLDL-cholesterol of 0.09-3.78 (median 0.92), IDL-cholesterol of 0.15-1.58 (median 0.45), and HDL-cholesterol of 0.36-2.28 (median 0.93). LDLcholesterol derived from ultracentrifugation data ranged from 1.13 to 7.27 (median 3.92) mmol/L.

Thirty-six specimens (18%) had a LDL-cholesterol calculated from the Friedewald formula that differed from the ultracentrifugation value by >10%. This proportion of specimens with significant error is similar to those proportions (15-19%) found in much larger series of patients of more diverse clinical conditions [12,13]. The proportion is substantially less than the 42% of 45 individuals with chronic renal failure reported by others [8], despite the lower lipid values in their series.

Recognition that the Friedewald formula is unreliable in the presence of chylomicronemia and hypertriglyceridemia has led to the use of various indices for the exclusion of such specimens. Total triglyceride concentration commonly is used [5], although a low total cholesterol:triglyceride ratio has been proposed as a more relevant criterion for rejection [14]. Additionally, others have identified increased cholesterol:triglyceride ratios in VLDL and IDL and increased IDL-cholesterol alone as being associated with increased error in the formula [8].

We plotted the number of errors detected against each index arranged in centiles (Fig. 1). The median (range) for each index was: total triglyceride concentration, 2.01 (0.48-7.74) mmol/L; total cholesterol: triglyceride ratio, 2.92 (0.86-7.86); cholesterol:triglyceride ratio in VLDL, 0.75 (0.31-1.28); IDL-cholesterol 0.45 (0.15-1.58) mmol/L; cholesterol:triglyceride ratio in IDL, 2.69 (1.11-6.80). With total triglyceride concentration and total cholesterol: triglyceride ratio (by inverse ranking so that increased incidence of error was positively associated with the index), error detection was similar with the number of errors initially small but rising steeply from the 60th centile. By contrast, with the ratio of cholesterol: triglyceride in VLDL and in IDL and with IDL-cholesterol concentration, the errors were more evenly distributed among the centiles. Quantitatively, 18 errors (50%) were included when triglyceride concentration was 3.51 mmol/L (86th centile), total cholesterol: triglyceride ratio was 1.91 (81st centile), cholesterol:triglyceride ratio in VLDL was 0.82 (70th centile), IDL-cholesterol was 0.53 mmol/L (65th centile), and cholesterol:triglyceride ratio in IDL was 2.51 (38th centile).


The ranking by total triglyceride concentration and total cholesterol: triglyceride ratio demonstrates that these values are far better suited as criteria for deciding whether it is valid to calculate LDL-cholesterol. Moreover, the results confirm that total triglyceride concentration alone seems to be the most simple and appropriate criterion to use, with total cholesterol: triglyceride ratio offering no improvement in discrimination.

In our study, 24 of 41 specimens (59%) with triglyceride concentration >3.2 mmol/L had an unreliable estimate of LDL-cholesterol from the Friedewald formula, with all but two being an overestimate. While such overestimation is typical of abnormal VLDL composition as seen in Type III hyperlipoproteinemia [5], there appeared to be no clear association between cholesterol:triglyceride ratio in VLDL and the incidence of error (Fig. 1). It seems improbable that the disparity between our results and those of others [8] could be explained by effects of drug treatment. Indeed, the conclusion was unchanged when the 50 specimens from patients on an hydroxymethylglutarylCoA reductase inhibitor were removed from analysis.

In summary, use of the Friedewald formula in a group of patients expected to give aberrant results provided reliable data in the majority of cases. Moreover, triglyceride concentration was a suitable index of reliability. However, restricting use of the formula to those specimens having a triglyceride concentration of <4.5 mmol (4 g)/L [13] included a group above the 80th centile in which the error rate exceeded 50%. Limiting use of the formula to those below the 80th centile and having a triglyceride concentration of <3.2 mmol (2.8 g)/L excluded the majority of errors and left 151 of 163 (93%) with a valid estimate. By contrast with the results of others [8,14], we found little influence of VLDL or IDL on the reliability of the Friedewald formula and no advantage with total cholesterol: triglyceride ratio as a discriminant.

The study of the effects of simvastatin and enalapril on serum lipoprotein concentrations in patients on dialysis, from which this work derives, was supported by a grant from Merck, Sharp and Dohme.


[1.] Castelli WP, Garrison RJ, Wilson PWF, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. J Am Med Assoc 1986;256:2835-8.

[2.] Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men. Lancet 1986;ii:933-6.

[3.] National Cholesterol Education Program Expert Panel. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). J Am Med Assoc 1993;269:3015-23.

[4.] Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.

[5.] Rifai N, Warnick GR, McNamara JR, Belcher JD, Grinstead GF, Frantz ID Jr. Measurement of low-density-lipoprotein cholesterol in serum: a status report. Clin Chem 1992;38:150-60.

[6.] Nestel PJ, Fidge NH, Tan MH. Increased lipoprotein-remnant formation in chronic renal failure. N Engl J Med 1982;307:329-33.

[7.] Ron D, Oren I, Aviram M, Better OS, Brook JG. Accumulation of lipoprotein remnants in patients with chronic renal failure. Atherosclerosis 1983;46: 67-75.

[8.] Senti M, Pedro-Botet J, Nogues X, Rubies-Prat J. Influence of intermediatedensity lipoproteins on the accuracy of the Friedewald formula. Clin Chem 1991;37:1394-7.

[9.] Robson R, Collins J, Johnson R, et al. on behalf of the PERFECT study collaborative group. Effects of simvastatin and enalapril on serum lipoprotein concentrations and left ventricular mass in patients on dialysis. J Neph rol 1997;10:33-40.

[10.] Lopes-Virella MF, Stone P, Ellis S, Colwell JA. Cholesterol determination in high density lipoproteins separated by three different methods. Clin Chem 1977;23:882-4.

[11.] Mills GL, Lane PA, Weech PK. A guidebook to lipoprotein technique. In: Burdon RH, van Knippenberg PH, eds. Laboratory techniques in biochemistry and molecular biology, Vol. 14. Amsterdam: Elsevier, 1984:18-116.

[12.] Warnick GR, Knopp RH, Fitzpatrick V, Branson L. Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints. Clin Chem 1990;36:15-9.

[13.] McNamara JR, Cohn JS, Wilson PWF, Schaefer EJ. Calculated values for low-density lipoprotein cholesterol in the assessment of lipid abnormalities and coronary disease risk. Clin Chem 1990;36:36-42.

[14.] Gonzalez G'-Estrada M, Rodriguez Ferrer CR, Recalde Astarloa I, Montalvo Lahera E. Use of serum cholesterol/triglyceride ratio to discern for which individuals the Friedewald formula can be used confidently. Clin Chem 1990;36:1673-5.

Roger Johnson, * Prudence McNutt, Stephen MacMahon, (1) and Richard Robson (2) (Dept. of Clin. Biochem., Natl. Women's Hosp., Private Bag 92189, Auckland 3, New Zealand;

(1) Clin. Trials Res. Unit, Univ. of Auckland, Auckland; and

(2) Dept. of Nephrol., Christchurch Hosp., Christchurch, New Zealand; author for correspondence: fax 64-9-6309996)
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Title Annotation:Technical Briefs
Author:Johnson, Roger; McNutt, Prudence; MacMahon, Stephen; Robson, Richard
Publication:Clinical Chemistry
Date:Nov 1, 1997
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