TRANSCRIPTIONAL LANDSCAPE OF METAL TRANSPORTER GENES AND POTENTIALLY TOXIC ELEMENTS EXPOSURE IN CKDU

Background and Aims:

Toxic metals, widely derived from diverse industries, insidiously build up in the body. It remains unclear whether these increased levels are a cause or a consequence. This study probed the influence of toxic metals and associated transporter genes on the etiology of chronic kidney disease of unknown etiology (CKDu), with a particular emphasis on the function of metal transporters.

Methods:

The study encompassed 211 CKDu patients and 214 controls, matched for age and sex. We analyzed blood samples for toxic metals, gene expressions, and kidney function tests. The quantification of toxic metals was performed using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). We assessed the gene expressions of biomarkers (MT2 and DMT1) via qRT-PCR. The quantification was executed using the 2^-ΔCT method. For the analysis of toxic metals in urine, urine samples were adjusted with urinary creatinine .

Results:

In our study, we observed elevated levels of toxic metals in patients with CKDu. Specifically, the median levels in CKDu patients were significantly increased as follows: aluminum (32.32 vs 13.44), nickel (5.04 vs 1.26), arsenic (4.04 vs 0.79), cadmium (3.17 vs 0.1), mercury (16.17 vs 7.55), and lead (1.58 vs 0.24). Similarly, CKDu patients had significantly higher levels of creatinine-adjusted urinary metal median levels as follows: aluminum (2.96 vs 1.92), nickel (0.35 vs 0.22), arsenic (1.32 vs 0.39), cadmium (0.59 vs 0.19), mercury (0.06 vs 0.07), and lead (0.09 vs 0.07).

The metal transporter genes including DMT gene (2.50-fold, p=0.01) and MT2 (1.54-fold, p=0.02) genes were overexpressed among CKDu patients. Multivariate analysis revealed only DMT along with three toxic metals i.e. Al, Hg and Pb were independently associated with eGFR.

Conclusion:

Out of seven, screened toxic metals (Al, Hg, Pb, Ni, Cd and As), only Cd, Hg and Pb along with DMT gene expression were independently associated with eGFR as revealed from multivariate analysis. Their increased serum concentration is leading to high urinary concentration, supported by enhanced gene expression of DMT and MT2 genes.