Clonal hematopoiesis -a novel opportunity to targetcardiovascular diseasein chronic kidney disease?

Background: Chronic kidney disease (CKD) confersan elevated risk of premature death,mainly attributed to cardiovascular disease (CVD).Recent studies show that age-associated somatic mutations causing clonal expansions of hematopoietic stem cells, so called clonal hematopoiesis of indeterminate potential (CHIP), are causatively linked to inflammationand CVD. The CHIP-CVD link has not beenstudiedin CKD.
Hypothesis:We hypothesize that CHIP accumulatesin the uremic milieuat an earlier chronological age than in the general population,contributing to an increasedCVD risk over and above that captured by traditional CVD risk factors alone.
Methods: 100 CKD patients (median age 47[range 19-75] years, 31% females) drawn from aprospective cohort with patients undergoing living donor kidney transplantation (KTx) wereincluded.Biobank samples and data on inflammation, senescence, uremic toxins and cardiovascular endpoints werecollected priorKTxand after 1 and 2 years.Low-frequency variants in23 commonly mutated genesin CHIPwereevaluated in blood using sensitive error-corrected sequencing on Illumina NovaSeq (BEA/SciLife lab). Skeletal muscle from the same patients wasused asnon-hematopoietic control tissue.Only variants with mutant allele fraction reaching at least 2% in bloodbut absent or rare in musclewere defined as CHIP.
Results: So far,baseline samples fromten patients (aged 60-70)have been sequenced.We identified and validatedputative CHIP-driving mutationslocated in TET2, ASXL1andJAK2intwo (20%)patients.Further analyses are ongoing.
Conclusions: These preliminary data suggestthat the prevalence of CHIP is at least 20%in CKD, which is higher than thegeneral population aged > 65 years (10%–15%). If the upcominganalysesdefine arelationship between CHIP, inflammation and CVDriskin CKD, it should be further explored whether CKD patients carrying CHIP variants may benefit more fromtargeted anti-inflammatory interventions.Suchknowledgecould be implementedintonovel precision medicine strategiesaimingto reduce CVD morbidity and mortalityin CKD.