Homeostasis of β2-microglobulin in diabetics and non-diabetics with modest cadmium intoxication

Abstract

Beta-2-microglobulin (β<inf>2</inf>M) is released into plasma from nucleated cells, filtered by glomeruli, and degraded by proximal tubular cells (PTCs). Normally, < 1% of filtered β<inf>2</inf>M is excreted in urine. Intoxication of PTCs by cadmium (Cd) reduces degradation and increases excretion of β<inf>2</inf>M (TD<inf>β2M</inf> and E<inf>β2M</inf>). Diabetes may exacerbate these effects or produce them independently. Herein, we normalized fluxes to creatinine clearance (C<inf>cr</inf>) to quantify amounts of β<inf>2</inf>M excreted and degraded per volume of filtrate (E<inf>β2M</inf>/C<inf>cr</inf> and TD<inf>β2M</inf>/C<inf>cr</inf>). We then performed a case-control study of diabetics (DM, n = 65) and non-diabetics (CTRL, n = 72) with modest Cd exposure. β<inf>2</inf>M influx (I<inf>β2M</inf>, equated with β<inf>2</inf>M filtration rate), serum β<inf>2</inf>M ([β<inf>2</inf>M]<inf>s</inf>), and TD<inf>β2M</inf>/C<inf>cr</inf> were higher in DM. Fractional tubular degradation of filtered β<inf>2</inf>M (FrTD<inf>β2M</inf>) emerged as the least confounded descriptor of PT β<inf>2</inf>M processing, and low values of FrTD<inf>β2M</inf> were seen in a subset of diabetics with minimal Cd intoxication. FrTD<inf>β2M</inf> varied inversely with E<inf>Cd</inf>/C<inf>cr</inf> in DM and directly with estimated GFR (eGFR) in DM and CTRL. In both groups, E<inf>β2M</inf>/C<inf>cr</inf> was inversely related to eGFR and FrTD<inf>β2M</inf>, but at any value of FrTD<inf>β2M</inf>, E<inf>β2M</inf>/C<inf>cr</inf> varied by a large multiple. We conclude that in subjects with modest Cd intoxication, I<inf>β2M</inf> was variable in DM and CTRL and higher in DM; FrTD<inf>β2M</inf> was related inversely to E<inf>Cd</inf>/C<inf>cr</inf> in DM and directly to eGFR in DM and CTRL; and E<inf>β2M</inf>/C<inf>cr</inf> varied inversely with eGFR and FrTD<inf>β2M</inf> in both groups. E<inf>β2M</inf>/C<inf>cr</inf>did not depict FrTD<inf>β2M</inf> precisely. We recommend FrTD<inf>β2M</inf> as an indicator of proximal tubular dysfunction.