Potential diagnostic biomarkers for chronic kidney disease of unknown etiology (CKDu) in Sri Lanka: a pilot study

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Abstract

Background

In Sri Lanka, there exists chronic kidney disease of both known (CKD) and unknown etiologies (CKDu). Identification of novel biomarkers that are customized to the specific causative factors would lead to early diagnosis and clearer prognosis of the diseases. This study aimed to find genetic biomarkers in blood to distinguish and identify CKDu from CKD as well as healthy populations from CKDu endemic and non-endemic areas of Sri Lanka.

Methods

The expression patterns of a selected panel of 12 potential genetic biomarkers were analyzed in blood using RT-qPCR. Fold changes of gene expressions in early and late stages of CKD and CKDu patients, and an apparently healthy population of a CKDu endemic area, Girandurukotte (GH) were calculated relative to apparently healthy volunteers from a CKDu non-endemic area, Kandy (KH) of Sri Lanka, using the comparative CT method.

Results

Significant differences were observed between KH and early stage CKDu for both the insulin-like growth factor binding protein 1 (IGFBP1; p = 0.012) and kidney injury molecule-1 (KIM1; p = 0.003) genes, and KH and late stage CKD and CKDu for the glutathione-S-transferase mu 1 (GSTM1; p < 0.05) gene. IGFBP1 and KIM1 genes showed significant difference between the early and late stage CKDu ( p < 0.01). The glutamate cysteine ligase catalytic subunit (GCLC) gene had significantly different expression between KH and all the other study groups ( p < 0.01). The GH group was significantly different from the KH group for the oxidative stress related genes, G6PD, GCLC and GSTM1 ( p < 0.01), and also the KIM1 gene ( p = 0.003). IGFBP1, insulin-like growth factor binding protein 3 (IGFBP3), fibronectin 1 (FN1) and KIM1 showed significant correlations with serum creatinine, and IGFBP1, KIM1 and kallikrein 1 (KLK1) with eGFR ( p < 0.05).

Conclusion

A panel consisting of IGFBP1, KIM1, GCLC and GSTM1 genes could be used in combination for early screening of CKDu, whereas these genes in addition with FN1, IGFBP3 and KLK1 could be used to monitor progression of CKDu. The regulation of these genes has to be studied on larger populations to validate their efficiency for further clinical use.

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Most cited references 42

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Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country

Nihal Jayatilake, Shanthi Mendis, Palitha Maheepala … (2013)

Background This study describes chronic kidney disease of uncertain aetiology (CKDu), which cannot be attributed to diabetes, hypertension or other known aetiologies, that has emerged in the North Central region of Sri Lanka. Methods A cross-sectional study was conducted, to determine the prevalence of and risk factors for CKDu. Arsenic, cadmium, lead, selenium, pesticides and other elements were analysed in biological samples from individuals with CKDu and compared with age- and sex-matched controls in the endemic and non-endemic areas. Food, water, soil and agrochemicals from both areas were analysed for heavy metals. Results The age-standardised prevalence of CKDu was 12.9% (95% confidence interval [CI] = 11.5% to 14.4%) in males and 16.9% (95% CI = 15.5% to 18.3%) in females. Severe stages of CKDu were more frequent in males (stage 3: males versus females = 23.2% versus 7.4%; stage 4: males versus females = 22.0% versus 7.3%; P 39 years and those who farmed (chena cultivation) (OR [odds ratio] = 1.926, 95% CI = 1.561 to 2.376 and OR = 1.195, 95% CI = 1.007 to 1.418 respectively, P < 0.05). The risk was reduced in individuals who were male or who engaged in paddy cultivation (OR = 0.745, 95% CI = 0.562 to 0.988 and OR = 0.732, 95% CI = 0.542 to 0.988 respectively, P < 0.05). The mean concentration of cadmium in urine was significantly higher in those with CKDu (1.039 μg/g) compared with controls in the endemic and non-endemic areas (0.646 μg/g, P < 0.001 and 0.345 μg/g, P < 0.05) respectively. Urine cadmium sensitivity and specificity were 70% and 68.3% respectively (area under the receiver operating characteristic curve = 0.682, 95% CI = 0.61 to 0.75, cut-off value ≥0.397 μg/g). A significant dose–effect relationship was seen between urine cadmium concentration and CKDu stage (P < 0.05). Urine cadmium and arsenic concentrations in individuals with CKDu were at levels known to cause kidney damage. Food items from the endemic area contained cadmium and lead above reference levels. Serum selenium was <90 μg/l in 63% of those with CKDu and pesticides residues were above reference levels in 31.6% of those with CKDu. Conclusions These results indicate chronic exposure of people in the endemic area to low levels of cadmium through the food chain and also to pesticides. Significantly higher urinary excretion of cadmium in individuals with CKDu, and the dose–effect relationship between urine cadmium concentration and CKDu stages suggest that cadmium exposure is a risk factor for the pathogensis of CKDu. Deficiency of selenium and genetic susceptibility seen in individuals with CKDu suggest that they may be predisposing factors for the development of CKDu.

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Biomarkers of renal function, which and when?

Michael E Wasung, Lakhmir S Chawla, Magdalena Madero (2015)

Acute kidney injury (AKI) and chronic kidney disease (CKD) are conditions that substantially increase morbidity and mortality. Although novel biomarkers are being used in practice, the diagnosis of AKI and CKD is still made with surrogate markers of GFR, such as serum creatinine (SCr), urine output and creatinine based estimating equations. SCr is limited as a marker of kidney dysfunction in both settings and may be inaccurate in several situations, such as in patients with low muscle mass or with fluid overload. New biomarkers have the potential to identify earlier patients with AKI and CKD and in the future potentially intervene to modify outcomes.

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Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis.

Benjamin Humphreys, Fengfeng Xu, Venkata Sabbisetti … (2013)

Acute kidney injury predisposes patients to the development of both chronic kidney disease and end-stage renal failure, but the molecular details underlying this important clinical association remain obscure. We report that kidney injury molecule-1 (KIM-1), an epithelial phosphatidylserine receptor expressed transiently after acute injury and chronically in fibrotic renal disease, promotes kidney fibrosis. Conditional expression of KIM-1 in renal epithelial cells (Kim1(RECtg)) in the absence of an injury stimulus resulted in focal epithelial vacuolization at birth, but otherwise normal tubule histology and kidney function. By 4 weeks of age, Kim1(RECtg) mice developed spontaneous and progressive interstitial kidney inflammation with fibrosis, leading to renal failure with anemia, proteinuria, hyperphosphatemia, hypertension, cardiac hypertrophy, and death, analogous to progressive kidney disease in humans. Kim1(RECtg) kidneys had elevated expression of proinflammatory monocyte chemotactic protein-1 (MCP-1) at early time points. Heterologous expression of KIM-1 in an immortalized proximal tubule cell line triggered MCP-1 secretion and increased MCP-1-dependent macrophage chemotaxis. In mice expressing a mutant, truncated KIM-1 polypeptide, experimental kidney fibrosis was ameliorated with reduced levels of MCP-1, consistent with a profibrotic role for native KIM-1. Thus, sustained KIM-1 expression promotes kidney fibrosis and provides a link between acute and recurrent injury with progressive chronic kidney disease.

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Author and article information

Contributors

Saravanabavan Sayanthooran: sayan_28@yahoo.com

Dhammika N. Magana-Arachchi: dmaganaarachchi@gmail.com

Lishanthe Gunerathne: lishanthe@yahoo.co.uk

Tilak Abeysekera: tilak_1@hotmail.com

Journal

Journal ID (nlm-ta): BMC Nephrol

Journal ID (iso-abbrev): BMC Nephrol

Title: BMC Nephrology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2369

Publication date (Electronic): 19 January 2017

Publication date PMC-release: 19 January 2017

Publication date Collection: 2017

Volume: 18

Electronic Location Identifier: 31

Affiliations

[1 ]ISNI 0000 0004 0636 3697, GRID grid.419020.e, Cell Biology Group, , National Institute of Fundamental Studies, ; Kandy, Sri Lanka

[2 ]Renal Care & Research Centre, District Hospital, Girandurukotte, Sri Lanka

[3 ]ISNI 0000 0000 9816 8637, GRID grid.11139.3b, Department of Pharmacology, Faculty of Medicine, , University of Peradeniya, ; Kandy, Sri Lanka

Article

Publisher ID: 440

DOI: 10.1186/s12882-017-0440-x

PMC ID: 5244589

PubMed ID: 28103909

SO-VID: 25937e59-ec0f-4128-b841-9fa41e40041a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 25 January 2016

Date accepted : 6 January 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100008968, National Research Council Sri Lanka;

Award ID: 11-059

Custom metadata

ScienceOpen disciplines: Nephrology

Keywords: gene expression analysis,kidney injury,oxidative stress,rt-qpcr

Data availability:

ScienceOpen disciplines: Nephrology

Keywords: gene expression analysis, kidney injury, oxidative stress, rt-qpcr

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Potential diagnostic biomarkers for chronic kidney disease of unknown etiology (CKDu) in Sri Lanka: a pilot study

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Karger: Nephrology

Most cited references 42

Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country

Biomarkers of renal function, which and when?

Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis.

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