1. Systematic Review of Beta 2 Microglobulin Population Kinetics
Christos Argyropoulos1, Maria-Eleni Roumelioti1, Thomas D. Nolin2 and Mark Unruh1. 1) Division of Nephrology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, and
2) Department of Pharmacy and Therapeutics, and Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh Schools of Pharmacy and Medicine, Pittsburgh, PA
Results
Background
Population Parameter Estimates of Beta 2 Microglobulin Kinetic Model
Population Distribution Values
Kinetic Parameter
Number (studies)
N (measurements/
Patients)
Median
Q25
Q75
Generation Rate (mg/kg/day),G
8 [69,70,80,85–90]
146 / 96
3.01
1.57
5.78
Intracompartmental Rate Transfer (ml/min), KIC
6 [33,69,80,85,86,88]
73 / 63
68.54
39.37
119.3
Extrarenal Clearance, Cl (ml/min), KER
6 [69,70,86–90]
59 / 56
2.92
1.37
6.25
Total Body Cl in Controls (ml/min), KER+KR
3 [70,85,88,89]
19 / 19
90.43
62.1
131.7
Total Volume of Distribution, TVD (L), VNP+VP
6 [33,69,70,80,85,86,89]
79 / 69
11.14
6.57
18.90
TVD (% BW)
5 [69,70,80,85,86,89]
69 / 59
17.73
11.13
28.24
Perfusing Compartment Volume, PCV (% BW), VNP
4.67
3.47
6.28
Ratio Of Non-perfusing to PCV, ΦNP
2.72
1.78
4.15
Table 1
Beta 2 Microglobulin (β2Μ) is a middle molecule associated with a higher risk of death in hemodialysis and chronic kidney disease patients (CKD).
It has long been appreciated that glomerular filtration is the major pathway for β2Μ elimination, so that renal function appears to be a significant factor affecting β2Μ concentration in these patients.
A quantitative understanding of β2Μ at the population level is lacking.
Objectives
We did a quantitative meta-analysis of studies with patient level data about β2Μ generation, distribution and elimination in humans.
Study Design
Studies of β2Μ kinetics were identified by searching MEDLINE with the following string: “(beta 2 microglobulin) AND (kinetic OR kinetics OR model OR models) AND (mathematical OR compartmental OR compartment OR simulation) AND (volume OR generation OR clearance OR dialysis OR renal OR dialytic OR production)” supplemented by manual inspection of the bibliography of identified papers.
We included papers if they had used a compartmental model for β2Μ kinetics, reported individual level data and were published in English.
We extracted data about each of the distinct parameters of a bicompartmental model for β2Μ population kinetics in CKD and hemodialysis [Figure 1A] for each patient in the study
We used a random effects model to estimate the mean and the standard deviation independently for each parameter
Ten papers reporting 9 separate studies fulfilled the criteria for inclusion (References).
Renal function was the major determinant of total body β2Μ clearance In table 1 we summarize estimates for the population distribution values (median, upper, Q95 and lower, Q25, 2.5% tail).
Only 5% of the simulated values were outside the upper limit of the reference range of β2Μ (3 mg/l)
Predicted correlations between GFR and 1/β2Μ were similar to those reported in the literature [Table 2]
β2Μ increased as renal function declined [Figure 1B]
In anuric HD patients, β2Μ was higher in those on low flux dialysis, but there was substantial overlap [Figure 1C]
Conclusions
We developed and estimated a population kinetic model for β2Μ
Model reproduces the reference range of β2Μ and the correlation between serum β2Μ and renal clearance
RRF is a major determinant of the levels of beta 2 macroglobulin in CKD
Model provides prediction about the effects of low and high flux dialysis on β2Μ that are in agreement with measurements in patient cohorts
This model could facilitate allow personalization of hemodialysis prescription using non-traditional forms of dialysis (short daily, extended duration, or hemodiafiltration)
Study
GFR Measure
Correlation
This report KR
0.76
Nephron. 1981;29(1-2):30-35
Iothalamate Clearance
0.90
J. Clin. Pathol. 1990;43(5):
51Cr-EDTA
0.79
Acta Med Scand. 1985;218(5):
0.59
Ren Fail. 2003;25(1):
Creatinine Clearance
0.80
0.87
Ren Fail. 2001;23(3-4):
99mTc-DTPA
J Pharm Biomed Anal. 2001;24(5-6):
0.73
References
Table 2
Int J Artif Organs. 2002;25(5):411–420.
Kidney Int. 2006;69(8):1431–1437.
Kidney Int. 1991;39(5):909–919.
Kidney Int Suppl. 1993;41:S83–87.
Eur J Clin Invest. 1980;10(4):293–300.
Acta Clin Belg Suppl. 1980;35:2–12.
Nephron. 1990;56(2):118–125.
J Lab Clin Med. 1991;118(2):153–165.
Kidney Int. 1992;42(6):1434–1443.
ASAIO J. 2001;47(6):623–627.
Figure 1