Metals and Metallothionein Expression in Relation to Progression of Chronic Kidney Disease of Unknown Etiology (CKDu) in Sri Lanka

Abstract

Chronic kidney disease of unknown etiology was investigated for metal relations in an endemic area by a cross-sectional study with CKD stages G1, G2, G3a, G3b, G4, G5 (ESRD), and endemic and nonendemic controls (EC and NEC) as groups. Subjects with the medical diagnosis were classified into groups by eGFR (SCr, CKD-EPI) and UACR of the study. It determined 24 metals/metalloids in plasma (ICPMS) and metallothionein (MT) mRNA in blood (RT-PCR). MT1A at G3b and MT2A throughout G2–G5 showed increased transcription compared to NEC (ANOVA, p < 0.01). Both MT1A and MT2A remained metal-responsive as associations emerged between MT2A and human MT inducer Cr (in EC: r = 0.54, p < 0.05, n = 14), and between MT1A and MT2A (in EC pooled with G1–G5: r = 0.58, p < 0.001, n = 110). Human MT (hMT)-inducers, namely Zn, Cu, As, Pb, and Ni; Σ hMT-inducers; 14 more non-inducer metals; and Σ MT-binding metals remained higher (p < 0.05) in EC as compared to NEC. Declining eGFR or CKD progression increased the burden of Be, Mg, Al, V, Co, Ni, Rb, Cs, Ba, Mn, Zn, Sr, Σ hMT-inducers, and Σ MT-binding metals in plasma, suggesting an MT role in the disease. MT1A/2A mRNA followed UACR (PCA, Dendrogram: similarity, 57.7%). The study provides evidence that proteinuric chronic renal failure may increase plasma metal levels where blood MT2A could be a marker.

Chronic kidney disease with unknown cause across the global spectrum

“…Males dominate over females by 1.2 to more than 3 : 1; rarely female individuals slightly predominate in select geographic regions [4,13]. The age at initial diagnosis is 20–60 years, with Asian patients trending older than those in Central America [3 ▪▪ ,8,13,14]. Sugarcane farming confers increased risk for CKDu in Central America while in Asia, it is rice paddy work [15].…”

“…However, other studies have shown rice with acceptable levels of lead, cadmium, and arsenic consumed by CKDu patients, suggesting this is not a primary disease mechanism [33]. Heavy metals and/or trace elements can contaminate agrochemicals resulting in simultaneous nephrotoxin exposures [14]. High fluoride levels have been found in black tea and groundwater in CKDu hot spots [6,7 & ].…”