Telomere attrition, kidney function, and prevalent chronic kidney disease in the United States

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Abstract

Background

Telomere length is an emerging novel biomarker of biologic age, cardiovascular risk and chronic medical conditions. Few studies have focused on the association between telomere length (TL) and kidney function.

Objective

We investigated the association between TL and kidney function/prevalent chronic kidney disease (CKD) in US adults.

Methods

The National Health and Nutrition Examination Survey (NHANES) participants with measured data on kidney function and TL from 1999 to 2002 were included. Estimated glomerular filtration rate (eGFR) was based on CKD Epidemiology Collaboration (CKD-EPI) equation. Urinary albumin excretion was assessed using urinary albumin-creatinine ratio (ACR). We used multivariable adjusted linear and logistic regression models, accounting for the survey design and sample weights.

Results

Of the 10568 eligible participants, 48.0% ( n=5020) were men. Their mean age was 44.1 years. eGFR significantly decreased and ACR significantly increased across increasing quarters of TL (all p<0.001). The association between TL and kidney function remained robust even after adjusting for potential confounding factors, but the association between TL and ACR was only borderline significant (β-coefficient= -0.012, p=0.056).

Conclusion

The association of kidney function with a marker of cellular senescence suggests an underlying mechanism influencing the progression of nephropathy.

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Most cited references 23

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Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths.

Masayuki Kimura, Rivka Stone, Steven Hunt … (2010)

In this protocol we describe a method to obtain telomere length parameters using Southern blots of terminal restriction fragments (TRFs). We use this approach primarily for epidemiological studies that examine leukocyte telomere length. However, the method can be adapted for telomere length measurements in other cells whose telomere lengths are within its detection boundaries. After extraction, DNA is inspected for integrity, digested, resolved by gel electrophoresis, transferred to a membrane, hybridized with labeled probes and exposed to X-ray film using chemiluminescence. Although precise and highly accurate, the method requires a considerable amount of DNA (3 μg per sample) and it measures both the canonical and noncanonical components of telomeres. The method also provides parameters of telomere length distribution in each DNA sample, which are useful in answering questions beyond those focusing on the mean length of telomeres in a given sample. A skilled technician can measure TRF length in ∼130 samples per week.

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Calibration of serum creatinine in the National Health and Nutrition Examination Surveys (NHANES) 1988-1994, 1999-2004.

Elizabeth Selvin, Jane Manzi, Lesley Stevens … (2007)

The calibration of serum creatinine values to standardized creatinine and the commutability of serum creatinine across surveys are essential to the correct use of National Health and Nutrition Examination Survey (NHANES) data for kidney function and for generating estimates of the burden of kidney disease in the United States. Calibration study of serum creatinine in NHANES III (1988-1994) and NHANES 1999-2000, 2001-2002, and 2003-2004 to directly compare creatinine measurements from the original surveys with standard creatinine measured using an assay traceable to known gold-standard methods. We also assessed predictors of differences between methods (potential interferences) in this general population. The NHANES are ongoing cross-sectional surveys of the civilian noninstitutionalized population of the United States. We selected random samples of approximately 200 stored specimens from persons aged 60 years or older from each survey (NHANES III, 1999-2000, 2001-2002, and 2003-2004). Stored serum specimens from the 4 NHANES surveys were analyzed for serum creatinine by using a Roche enzymatic assay implemented at the Cleveland Clinic Research Laboratory (CCRL). The Roche assay is traceable to gold-standard reference methods. The original NHANES serum creatinine values were obtained using the Jaffé method (kinetic alkaline picrate) implemented in several different laboratories. Overall agreement between the original NHANES values (Jaffé method) and CCRL measurements (Roche enzymatic) was high, but substantial biases were observed in NHANES III and 1999-2000. No bias was observed in NHANES 2001-2002 and 2003-2004. Final calibration equations to correct serum creatinine values in the relevant surveys are provided. Assay differences were independent of sex, race/ethnicity, and bilirubin and triglyceride levels, but weakly related to age and glucose concentration. We were not able to examine drift in measurements over time within each survey or directly evaluate freeze-thaw effects. The magnitude of differences in serum creatinine measurements in NHANES III and 1999-2000 from standard creatinine would result in large differences in estimates of kidney function (10% to 20%). Thus, correction of original creatinine values in NHANES III and 1999-2000 is essential, but no correction is needed for NHANES 2001-2002 or 2003-2004.

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Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions.

Shiran Yehezkel, Yardena Segev, Evani Viegas-Péquignot … (2008)

Telomeres and adjacent subtelomeric regions are packaged as heterochromatin in many organisms. The heterochromatic features include DNA methylation, histones H3-Lys9 (Lysine 9) and H4-Lys20 (Lysine 20) methylation and heterochromatin protein1 alpha binding. Subtelomeric DNA is hypomethylated in human sperm and ova, and these regions are subjected to de novo methylation during development. In mice this activity is carried out by DNA methyltransferase 3b (Dnmt3b). Mutations in DNMT3B in humans lead to the autosomal-recessive ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome. Here we show that, in addition to several satellite and non-satellite repeats, the subtelomeric regions in lymphoblastoid and fibroblast cells of ICF patients are also hypomethylated to similar levels as in sperm. Furthermore, the telomeres are abnormally short in both the telomerase-positive and -negative cells, and many chromosome ends lack detectable telomere fluorescence in situ hybridization signals from either one or both sister-chromatids. In contrast to Dnmt3a/b(-/-) mouse embryonic stem cells, increased telomere sister-chromatid exchange was not observed in ICF cells. Hypomethylation of subtelomeric regions was associated in the ICF cells with advanced telomere replication timing and elevated levels of transcripts emanating from telomeric regions, known as TERRA (telomeric-repeat-containing RNA) or TelRNA. The current findings provide a mechanistic explanation for the abnormal telomeric phenotype observed in ICF syndrome and highlights the link between TERRA/TelRNA and structural telomeric integrity.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 6 October 2017

Publication date (Electronic): 8 September 2017

Volume: 8

Issue: 46

Pages: 80175-80181

Affiliations

¹ Key State Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

² Institute of Genetics and Developmental Biology, International College, University of Chinese Academy of Science, Beijing, China

³ Nephrology Clinic, Parhon University Hospital, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania

⁴ Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, Bialystok, Poland

⁵ Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Zeromskiego, Lodz, Poland

⁶ Non-Communicable Disease Research Unit, South African Medical Research Council and University of Cape Town, Cape Town, South Africa

⁷ Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Lodz, Poland

⁸ Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland

Author notes

Correspondence to: Mohsen Mazidi, Moshen@ 123456genetics.ac.cn

Article

Publisher ID: 20706

DOI: 10.18632/oncotarget.20706

PMC ID: 5655188

PubMed ID: 29113293

SO-VID: 478e53c0-a6e0-424e-bd94-5af66a34e2af

License:

This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

Telomere attrition, kidney function, and prevalent chronic kidney disease in the United States

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Abstract

Background

Objective

Methods

Results

Conclusion

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Karger: Oncology

Most cited references 23

Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths.

Calibration of serum creatinine in the National Health and Nutrition Examination Surveys (NHANES) 1988-1994, 1999-2004.

Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions.

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