Kidney Transplantation Reverses Aging: Renal Rejuvenation

Researchers discovered that kidney transplantation (KT) reduces the consequences of renal aging in a new study published in the Journal of Internal Medicine.

Treating chronic kidney disease

Chronic kidney disease (CKD) is an age-related condition that causes accelerated aging. Because of the decreased clearance of uremic toxins during CKD, toxic solutes accumulate, contributing to endothelial dysfunction, chronic inflammatory load, and increased oxidative stress.

KT is now the greatest treatment for kidney failure; nevertheless, it has with certain drawbacks, including the danger of organ rejection/dysfunction, a limited kidney lifespan, and the necessity for immunosuppression. Similarly, dialysis has limits, such as a higher risk of infection, high costs, a lower quality of life, minimal efficacy, and an increased risk of extra oxidative stress and inflammation. Furthermore, whether dialysis or KT slows or reverses the aging process associated with CKD is unknown.

About the Study

Researchers used DNA methylation (DNAm), skin autofluorescence (SAF), and phenotypic age (PA) approaches to estimate the biological age of CKD patients at stages G3 (moderate loss in renal function) to G5 (kidney failure). The PA cohort included controls and patients with CKD at stages G3-4 and G5, whereas the DNAm cohort included controls and CKD G5 patients starting dialysis or KT. Patients with end-stage renal disease (ESKD) made up the SAF cohort.
Serum creatinine, albumin, interleukin 6 (IL-6), hemoglobin, high-sensitivity C-reactive protein (hs-CRP), white blood cell count, intact parathyroid hormone (iPTH), calcium, triglycerides, cholesterol, and phosphate were all measured at baseline.

PA was calculated using chronological age and nine biomarkers: CRP, albumin, alkaline phosphatase, leucocyte count, RBC volume, lymphocyte percentage, serum glucose, creatinine, and RBC distribution width.

SAF was measured using an Autofluorescence advanced glycation end products (AGE) reader during blood sample collection. Whole blood samples were collected from kidney failure patients at baseline, also known as pre-dialysis initiation or pre-KT, and one year later for DNAm analysis. DNA was extracted and tested for concentration and integrity.

DNAm was measured, and beta values were derived to show the percent methylation per locus. The beta values were used to calculate DNAm age using three DNAm clocks: the PhenoAge, Hannum, and Horvath clocks.

Each clock’s age acceleration, defined as the difference between chronological and DNAm age, was calculated. The subjects were tracked for 60 months, or until KT/death.

Study Findings

The researchers looked at PA in 333 people, 56.5% of whom were men, 24.6% of whom had cardiovascular disease (CVD), and 24% of whom had diabetes. PA and chronological age were found to be related in both controls and CKD G3-4 patients. The PA was high in the CKD G5 group, and the connection with chronological age was significant but low.

Elevated PA was linked to lower eGFR, albumin, hand grip strength (HGS), hemoglobin, high-density lipoprotein (HDL), and higher triglycerides, hs-CRP, systolic blood pressure, iPTH, and IL-6 levels.

The SAF cohort consisted of 199 people, 65.3% of whom were men. Diabetes or CVD affected approximately 20% of the SAF cohort.

In CKD G5 patients, the connection between chronological and SAF age was moderate. SAF age was linked to lower albumin and HGS and higher hs-CRP and IL-6 levels.

The DNAm cohort comprised of 47 people. The three DNAm clocks were accurate, and their median absolute error matched previous estimations.

The mean DNAm age, calculated as the sum of the three clocks, was 49.2. The average age difference between the KT and dialysis groups and the controls was 4.9 or 5.9 years, respectively. At baseline, there was a weak connection between chronological and DNAm age in the KT group compared to the dialysis and control groups.

In the KT and dialysis groups, the three clocks were associated with greater age acceleration than in the controls. One year after KT, phenoAge and composite DNAm age acceleration decreased significantly compared to baseline; however, there were no significant changes in age acceleration a year later. Notably, the KT group improved in kidney function metrics.

Conclusions

The outcomes of the study demonstrate that CKD causes rapid aging. Furthermore, SAF and PA were discovered to be inadequate aging biomarkers because they produce implausibly high biological age estimates.

Although SAF and PA correctly predict greater morbidity and death risks, they overstate their magnitude. DNAm clocks performed better, implying that DNAm may be a better biomarker for estimating biological age in CKD.

Using three epigenetic clocks and a composite average of the three clocks, ESKD patients show epigenetic age acceleration. The reduced sample size may explain the decreased link between chronological and DNAm aging in the KT group.

Furthermore, one year after KT, age acceleration was reduced, whereas dialysis had no effect on age acceleration.

For more information: Epigenetic clocks indicate that kidney transplantation and not dialysis mitigate the effects of renal aging. Journal of Internal Medicine.

doi:10.1111/joim.13724