M. Sonikian et al., POTENTIAL EFFECT OF METABOLIC-ACIDOSIS ON BETA-2-MICROGLOBULIN GENERATION - IN-VIVO AND IN-VITRO STUDIES, Journal of the American Society of Nephrology, 7(2), 1996, pp. 350-356
beta 2-Microglobulin (beta 2M) is responsible for dialysis-associated
amyloidosis. Levels of beta 2M in plasma increase during chronic renal
failure; however, retention does not appear to be the sole mechanism
responsible. The effect of metabolic acidosis on beta 2M production wa
s examined, Thirty-six patients with stable chronic renal insufficienc
y, 12 uremic patients before their first dialysis, 8 hemodialysis pati
ents who were assigned to acetate or bicarbonate dialysate and then cr
ossed over to the alternative regimen, and 6 normal subjects given NH4
Cl to initiate metabolic acidosis were studied. In vitro studies in th
e human myeloid cell line U 937 were also performed. beta 2M protein w
as measured with ELISA, beta 2M mRNA was measured with reverse transcr
iption polymerase chain reaction, and the U 937 cells were studied at
two pH levels with FACScan flow cytometry. The cells were exposed in v
itro up to 60 min in a buffered incubation medium to either pH 5.10 or
pH 7.34. An inverse correlation was found between beta 2M and bicarbo
nate concentrations in plasma in the stable chronic renal failure pati
ents (r = -0.54; P < 0.05) and in the uremic patients before their fir
st dialysis (r = -0.72; P < 0.05). In hemodialysis patients, blood pH
and plasma bicarbonate values were lower (P < 0.05) and beta 2M concen
trations in plasma were higher (P < 0.05) with acetate than with bicar
bonate dialysate. In normal men, NH4Cl resulted in an increase (P < 0.
05) in beta 2M mRNA expression in lymphocytes by an average factor of
1.5 (range, 1.1 to 1.8), In U 937 cells, the cell surface expression o
f beta 2M and HLA Class I heavy chain assembled with beta 2M decreased
at low pH compared with normal pH, Concomitantly, an increase in beta
2M release into the supernatant was observed, possibly as the result
of beta 2M dissociation from cell surface HLA Class I complex. The res
ults suggest that metabolic acidosis may enhance cellular beta 2M gene
ration and release.