Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post–lung transplantation survival

Abstract

Background Prior studies have shown that patients with pulmonary fibrosis with mutations in the telomerase genes have a high rate of certain complications after lung transplantation. However, few studies have investigated clinical outcomes by leukocyte telomere length. Methods We conducted an observational cohort study of all pulmonary fibrosis patients who underwent lung transplantation at a single center between January 1, 2007 and December 31, 2014. Leukocyte telomere length was measured from a sample of blood collected prior to lung transplantation and subjects were stratified into two groups (telomere length <10th versus ≥10th percentile). The primary outcome was post-lung transplant survival. Secondary outcomes included incidence of allograft dysfunction, non-pulmonary organ dysfunction and infection. Results Approximately one-third (32%) of subjects had a telomere length below the 10th percentile. Telomere length <10th percentile was independently associated with worse survival (HR 10.9, 95% CI 2.7–44.8, p=0.001). Telomere length <10th percentile was also independently associated with a shorter time to the onset of chronic lung allograft dysfunction (CLAD) (HR 6.3, 95% CI 2.0–20.0, p=0.002). Grade 3 primary graft dysfunction occurred more frequently in the <10th percentile group compared to the ≥10th percentile group (28% vs 7%, p=0.034). There was no difference in the incidence of acute cellular rejection, cytopenias, infection or renal dysfunction in the two groups. Conclusions Telomere length <10th percentile was associated with worse survival and shorter time to onset of CLAD, and thus represents a biomarker that may aid in the risk stratification of pulmonary fibrosis patients prior to lung transplantation.

Where the Chromosome Ends: Telomeres and Cytomegalovirus Risk in Lung Transplant Recipients

“…Such differences may explain discrepancies between the present findings and other cohorts. In this article, 71% of the patients with IPF had telomere lengths below the 10 th percentile, which is substantially higher than the 32% of IPF lung transplant recipients in the cohort described at UT Southwestern (14). The high incidence of biopsy-proven end-organ CMV disease in 17 of 84 subjects was also not reported in other cohorts.…”

“…An increased risk of CMV infection was not observed in recipients with short telomeres in the two prior cohort studies (13,14). At our center, recipients with short telomeres had increased rates of leukopenia requiring medication adjustment again did not have increased rates of CMV infection (7).…”

Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation

“…The potential contribution of telomerase complex gene variants to cytopenias could have significant implications for these patients after liver transplantation, as they take myelosuppressive medications to prevent transplant rejection and infection. Patients with telomerase complex mutations undergoing lung transplantation have increased risk of myelodysplasia and/or bone marrow failure, and shortened telomere length has been associated with worse survival and shorter time to lung allograft dysfunction, although the effect of telomere length on liver transplant outcomes is not known . Already, specific variants in the telomerase reverse transcriptase ( TERT ) gene have been observed at a higher frequency in patients with cirrhosis compared with healthy controls, affecting 2.7% of 521 patients with cirrhosis examined in one large study .…”

“…Patients with telomerase complex mutations undergoing lung transplantation have increased risk of myelodysplasia and/or bone marrow failure, and shortened telomere length has been associated with worse survival and shorter time to lung allograft dysfunction, although the effect of telomere length on liver transplant outcomes is not known. (3,4) Already, specific variants in the telomerase reverse transcriptase (TERT) gene have been observed at a higher frequency in patients with cirrhosis compared with healthy controls, affecting 2.7% of 521 patients with cirrhosis examined in one large study. (5) In another series of 134 patients with cirrhosis, 7% were found to have a missense TERT variant.…”

Do donors matter? Short telomeres and survival after lung transplant

“…Another study since then examined recipient TL specifically in patients with pulmonary fibrosis and divided the cohort into two groups of <10th percentile and ≥10th percentile TL and showed significantly worse survival in the <10th percentile even when controlling for other factors such as infection rate, ACR and primary graft dysfunction 8. Faust’s study adds to the field in that it has a longer follow-up and larger study population than previous studies which may account for why the prior studies did not find similar significance.…”