Dr Sayanthooran Saravanabavan1,2, Ms Alexandra Munt1,2, Dr. Sunil Badve3, Prof. Neil Boudville4, Ms Helen Coolican5, Dr. Susan Coulshed6, Ms. Sheryl Foster7,8, Dr. Mangalee Fernando9, Dr. Imad Haloob10, Prof. David Harris1,2, Prof. Carmel Hawley11,12, Dr. Jane Holt13, Dr. Martin Howell14, Dr. Karthik Kumar15, Prof. David Johnson11,12, Dr. Vincent Lee1,2, Dr. Maureen Lonergan13, Dr. Jun Mai17, Prof. Simon Roger18, Dr. Kamal Sud19, Dr. Allison Tong20, Prof. Vicente Torres21, Dr. Eswari Vilayur22, Prof. Gopala Rangan1,2
1Michael Stern Laboratory for Polycystic Kidney Disease, Westmead Institute for Medical Research, The University of Sydney, Westmead, Australia, 2Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Westmead, Australia, 3Department of Renal Medicine, St George Hospital, Kograh, Australia, 4Department of Renal Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia, 5PKD Australia, Roseville, Australia, 6North Shore Nephrology, Crows Nest, Australia, 7Department of Radiology, Westmead Hospital, Western Sydney Local Health District, Westmead, Australia, 8School of Health Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia, 9Department of Renal Medicine, Prince of Wales Hospital, Eastern Sydney Health District, Randwick, Australia, 10Department of Renal Medicine, Bathurst Hospital, Bathurst, Australia, 11Australasian Kidney Trials Network, University of Queensland at Princess Alexandra Hospital, Woolloongabba, Australia, 12Faculty of Medicine, Princess Alexandra Hospital Southside Clinical Unit, Woolloongabba, Australia, 13Department of Renal Medicine, Wollongong Hospital, Illawarra Shoalhaven Local Health District, Wollongong, Australia, 14School of Public Health, The University of Sydney, Sydney, Australia, 15Gosford Nephrology, Gosford, Australia, 16Department of Renal Medicine, Wollongong Hospital, Illawarra Shoalhaven Local Health District, Wollongong, Australia, 17Department of Renal Medicine, Liverpool Hospital, Southwestern Sydney Local Health District, Liverpool, Australia, 18Renal Research, Gosford, Australia, 19Department of Renal Medicine, Nepean Hospital, Nepean Blue Mountains Local Health District, Kingswood, Australia, 20Centre for Kidney Research, The Children’s Hospital at Westmead , Westmead, Australia, 21Translational Polycystic Kidney Disease Center, Mayo Clinic, Rochester, USA, 22Department of Nephrology, John Hunter Hospital, Newcastle, Australia
Aim. To test the hypothesis that peripheral blood mitochondrial DNA copy number (mtDNA-CN) is inversely associated with the severity of kidney disease in ADPKD.
Background. ADPKD is a single-gene disorder and the most common genetic cause of kidney failure in adults. The natural history of ADPKD demonstrates high inter-individual and intra-familial heterogeneity, and a simple and reliable prognostic biomarker is a major unmet need for patients with this condition. Mitochondrial dysfunction is a key secondary molecular feature of ADPKD, and reduced mtDNA-CN has been reported in experimental ADPKD.
Methods. Peripheral blood DNA was extracted from 187 ADPKD patients at the baseline of the PREVENT-ADPKD trial. MtDNA-CN was determined as a ratio of the mitochondrial gene, tRNA leucine (tRNAleu) to nuclear gene, β2-microglobulin (B2M) using real-time quantitative polymerase chain reaction (qPCR). Additionally, a gene array dataset of human ADPKD cystic tissue (National Center for Biotechnology Information Gene Expression Omnibus database; accession number GSE7869) was analysed to infer kidney-specific mitochondrial levels.
Results. The mean mtDNA-CN in the cohort was 96.5 ± 23.8. By univariate analysis, body mass index and 24-hour urine osmolality had a positive weak association with mtDNA-CN (r=0.22 and r=0.16 respectively; P<0.05). However, by multivariate analysis, mtDNA-CN was not associated with baseline markers of kidney disease severity (stage of chronic kidney disease and kidney volume, as estimated by magnetic resonance imaging). In contrast, bioinformatic analysis of gene expression from human ADPKD tissue revealed that the expression of genes regulating mitochondrial function was reduced.
Conclusion. These data suggest that mtDNA-CN measured by qPCR in peripheral blood does not predict the severity of ADPKD and may not reflect its expression in the kidney.
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