Increased Telomere Attrition After Renal Transplantation—Impact of Antimetabolite Therapy

Abstract

BackgroundThe uremic milieu exposes chronic kidney disease (CKD) patients to premature ageing processes. The impact of renal replacement therapy (dialysis and renal transplantation [RTx]) or immunosuppressive treatment regimens on ageing biomarkers has scarcely been studied.MethodsIn this study telomere length in whole blood cells was measured in 49 dialysis patients and 47 RTx patients close to therapy initiation and again after 12 months. Forty-three non-CKD patients were included as controls.ResultsNon-CKD patients had significantly (P ≤ 0.01) longer telomeres than CKD patients. Telomere attrition after 12 months was significantly greater in RTx patients compared to dialysis patients (P = 0.008). RTx patients receiving mycophenolate mofetil (MMF) had a greater (P = 0.007) degree of telomere attrition compared to those treated with azathioprine. After 12 months, folate was significantly higher in RTx patients than in dialysis patients (P < 0.0001), whereas the opposite was true for homocysteine (P < 0.0001). The azathioprine group had lower levels of folate after 12 months than the MMF group (P = 0.003).ConclusionsThe associations between immunosuppressive therapy, telomere attrition, and changes in folate indicate a link between methyl donor potential, immunosuppressive drugs, and biological ageing. The hypothesis that the increased telomere attrition, observed in the MMF group after RTx, is driven by the immunosuppressive treatment, deserves further attention.

Telomere length regulators are activated in young men after pediatric kidney transplantation compared to healthy controls and survivors of childhood cancer—A cross‐sectional study

“…We found further a significant positive correlation between increased gene expression of TRF2 and RPA1 and hsCRP, which supports the previous findings that deteriorating graft function and chronic inflammation may affect telomere stability in the KTx population. 18,21 To the best of our knowledge, this is the first study reporting the impact of pediatric KTx on telomere length and telomere-binding proteins at adult age.…”

“…End-stage kidney disease and immunosuppressive medication have been shown to shorten telomere length. [16][17][18]20 In the present study, we evaluated the telomere length and expression of genes encoding telomere-binding proteins in a cohort of young men with a history of long-lasting exposure to immunosuppressive medication due to KTx during childhood. The results were compared with those of healthy controls and with another control group comprising survivors of childhood NBL.…”

“…Previous studies have shown that telomere length is decreased in patients with ESRD as well as in young adults with a history of childhood cancer . According to Luttropp et al telomere length is shorter in KTx patients using MMF as antimetabolite therapy in comparison with those on either azathioprine or chronic dialysis. These findings suggest that telomere length and/or early aging is affected by ongoing chronic disease, such as ESRD, as well as by exposure to cytotoxic treatment or immunosuppressive medication.…”

The role of epigenetics in renal ageing

“…118 Recent evidence has indicated a link between immunosuppressive therapy, aging and homocysteine biochemistry in renal transplant recipients. 119 Longitudinal analyses of aging in CKD have indicated that these patients displayed significantly advanced biological age. 98 Notably, homocysteine is critical for DNA methylation nucleotide biosynthesis and maintenance of genomic integrity.…”

“…120,121 Impact on the cellular methylome in these circumstances seems intuitive, but requires further investigation to determine if any changes in its status either drive the accelerated aging, or are a consequence of it, or of any clinical interventions. 119 At a cellular level, recent evidence suggests an important role for the SASP in the pathogenesis of inflammaging. Senescent cells are pro-inflammatory 122 .…”