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International Urology and Nephrology
https://doi.org/10.1007/s11255-018-1892-z
NEPHROLOGY - ORIGINAL PAPER
Transcriptome analysis supports viral infection and fluoride toxicity
as contributors to chronic kidney disease of unknown etiology (CKDu)
in Sri Lanka
Saravanabavan Sayanthooran
1
· Lishanthe Gunerathne
2
· Tilak D. J. Abeysekera
3
·
Dhammika N. Magana‑Arachchi
1
Received: 8 February 2018 / Accepted: 10 May 2018
© Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract
Purpose Chronic kidney disease of unknown etiology (CKDu), having epidemic characteristics, is being diagnosed increas-
ingly in certain tropical regions of the world, mainly Latin America and Sri Lanka. They have been observed primarily in
farming communities and current hypotheses point toward many environmental and occupational triggers. CKDu does not
have common etiologies of chronic kidney disease (CKD) such as hypertension, diabetes, or autoimmune disease. We aimed
to understand the molecular processes underlying CKDu in Sri Lanka using transcriptome analysis.
Methods RNA extracted from whole blood was reverse transcribed and used for microarray analysis using the Human HT-12
v.4 array (Illumina). Pathway analysis was carried out using ingenuity pathway analysis (IPA—Qiagen). Microarray results
were validated using real-time PCR of five selected genes.
Results Pathways related to innate immune response, including interferon signaling, inflammasome signaling and TREM1
signaling had the most significant positive activation z scores, where as EIF2 signaling and mTOR signaling had the most
significant negative activation z scores. Pathways previously linked to fluoride toxicity; G-protein activation, Cdc42 signaling,
Rac signaling and RhoA signaling were activated in CKDu patients. The most significantly activated biological functions
were cell death, cell movement and antimicrobial response. Significant toxicological functions were mitochondrial dysfunc-
tion, oxidative stress and apoptosis.
Conclusions Based on the molecular pathway analysis in CKDu patients and review of literature, viral infections and fluoride
toxicity appear to be contributing to the molecular mechanisms underlying CKDu.
Keywords EIF2 signaling · Innate immunity · Interferon signaling · Microarray · mTOR signaling · RT-qPCR
Introduction
Chronic kidney disease (CKD) is a global public health
problem and the etiology for the disease is said to be affected
by racial, geographic and economic disparities [1, 2]. Sys-
temic diseases such as hypertension and diabetes contribute
to majority of the cases in all the developed countries and
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s1125 5-018-1892-z) contains
supplementary material, which is available to authorized users.
* Dhammika N. Magana-Arachchi
cellbio@ifs.ac.lk
Saravanabavan Sayanthooran
sayan_28@yahoo.com
Lishanthe Gunerathne
lishanthe@yahoo.co.uk
Tilak D. J. Abeysekera
tilak_1@hotmail.com
1
Molecular Microbiology and Human Diseases, National
Institute of Fundamental Studies, Kandy 20000, Sri Lanka
2
Renal Research Centre, District Hospital,
Girandurukotte 90750, Sri Lanka
3
Centre for Education, Research and Training on Kidney
Diseases (CERTKID), Faculty of Medicine, University
of Peradeniya, Peradeniya 20400, Sri Lanka
@Phil_Robichaud
@deepthiw
@JoseServera