The polymixin
colistin represents a last resort
antibiotic for multidrug resistant
infections, but its use is limited by the frequent onset of acute drug-induced kidney injury (DIKI). It is essential to closely monitor kidney function prior to and during
colistin treatment in order to pinpoint early signs of injury and minimise long-term renal dysfunction. To facilitate this, a mouse model of
colistin-induced nephrotoxicity was used to uncover novel early markers of
colistin-induced DIKI. Increased urinary levels of kidney injury molecule 1 (Kim-1) as well as
glycosuria were observed in
colistin-treated mice, where alterations of established
clinical markers of
acute kidney injury (serum
creatinine and
albuminuria) and emerging markers such as
cystatin C were inaccurate in flagging renal damage as confirmed by histology. A direct interaction of
colistin with renal
glucose reabsorption was ruled out by a cis-inhibition assay in mouse brush border membrane vesicles (BBMV). Immunohistochemical examination and
protein quantification by western blotting showed a marked reduction in the
protein amount of
sodium-glucose transporter 2 (Sglt2), the main kidney
glucose transporter, in renal tissue from
colistin-treated mice in comparison to control animals. Consistently, BBMV isolated from treated mouse kidneys also showed a reduction in ex vivo
glucose uptake when compared to BBMV isolated from control kidneys. These findings support pathology observations of
colistin-induced proximal tubule damage at the site of the brush border membrane, where Sglt2 is expressed, and open avenues for the study of
glycosuria as a sensitive, specific, and accessible marker of DIKI during
colistin therapy.