Kidney Week

Abstract: TH-OR39

Mitochondrial DNA Copy Number Is Associated with Incident AKI, CKD, and Inflammatory Biomarkers

Session Information

• CKD: Novel Risk Factors and Consequences
  October 24, 2024 | Location: Room 24, Convention Center
  Abstract Time: 04:50 PM - 05:00 PM

Category: CKD (Non-Dialysis)

• 2301 CKD (Non-Dialysis): Epidemiology, Risk Factors, and Prevention

Authors

• Gaheer, Pukhraj Singh, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada

Pukhraj Singh Gaheer

• Caltagirone, Giuliano, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada

Giuliano Caltagirone

• Levin, Adeera, The University of British Columbia, Vancouver, British Columbia, Canada

Adeera Levin, MD

• Deng, Wei Q., McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada

Wei Q. Deng, PhD

• Chong, Michael R., McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada

Michael R. Chong, MSc, PhD

• Lanktree, Matthew Bruce, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada

Matthew Bruce Lanktree, MD, PhD, FASN

Background

Mitochondrial DNA copy number (mtDNA-CN) is an estimate of the number of mitochondria per leukocyte and a surrogate measure of net mitochondrial function. Reduced mtDNA-CN has been reported associated with diabetes, cardiovascular disease, and CKD. We sought to evaluate the association of blood mtDNA-CN with incident acute kidney injury (AKI), CKD, and inflammatory biomarkers.

Methods

mtDNA-CN was estimated from whole-genome sequencing data in the UK Biobank cohort, consisting of 38,440 samples from the general population. We estimated mtDNA-CN using a quantitative polymerase chain reaction (qPCR) in the Canadian study of prediction of death, dialysis, and interim cardiovascular events (CanPREDDICT) cohort, consisting of 1,435 patients with advanced CKD. Linear and Cox proportional hazard regressions were adjusted for blood cell counts, age, sex, and comorbidities. We also used two-sample Mendelian randomization to test if genetically predicted mtDNA-CN was associated with eGFR. Reverse Mendelian randomization tested the opposite direction: if genetically predicted kidney function was associated with mtDNA-CN.

Results

In the UK Biobank, we observed a 12% higher risk of incident AKI (hazard ratio (HR)=0.88, 95% CI = 0.86–0.91, P=2.4x10^-6) and 8% increased odds of incident CKD (odds ratio=0.92, 95% CI = 0.89-0.94, P=0.0008) per 1 standard deviation (SD) decrease in mtDNA-CN while adjusting for baseline eGFR. Meta-analyzing across CanPREDDICT and UK Biobank revealed a 16% higher risk of incident kidney failure (HR=0.84, 95% CI = 0.76-0.93; P=0.0006) and a 3% increase in uACR (95% CI = 1%-5%, P=0.002) per 1 SD decrease in mtDNA-CN. In CanPREDDICT, mtDNA-CN was also associated with transforming growth factor-ß1 (TGFß1, ß=-9.5% per 1 SD decrease, P=0.0005) and C reactive protein (CRP, ß=8.9% per 1 SD decrease, P=0.005). Bidirectional Mendelian randomization analysis did not support either mtDNA-CN or eGFR as causally impacting the other (P>0.05).

Conclusion

mtDNA-CN was associated with incident AKI, CKD, and kidney failure, as well as pro-inflammatory markers TGFß1 and CRP. However, Mendelian randomization analysis did not support a causal relationship between kidney function and mtDNA-CN, suggesting a separate causal pathway mediates the association.

Funding

• Government Support – Non-U.S.