Science, Medicine, and the Anesthesiologist

Acute kidney injury after hypoperfusion is common and it has a higher occurrence in older patients but has not previously been clearly associated with genetic risk factors. Clonal hematopoiesis of indeterminate potential is a well-recognized phenomenon of aging that results from the clonal expansion of hematopoietic stem cells that have previously acquired mutations. Several of these mutated genes (DNMT3A, TET2, JAK2) have been associated with increased mortality in cardiovascular, pulmonary, and liver diseases and are associated with enhanced and sustained inflammatory organ injury. In the current study, these gene mutations associated with clonal hematopoiesis of indeterminate potential occurred in 3.4% of samples in the United Kingdom BioBank, were increased with age, and were associated with a 34% increased risk of acute kidney injury. Furthermore, clonal hematopoiesis of indeterminate potential was associated with a 20% increased risk of acute kidney injury in a meta-analysis of two prospective cohort studies, the Atherosclerosis Risk in Communities (ARIC) and the Cardiovascular Health Study (CHS). Clonal hematopoiesis of indeterminate potential was also associated with impaired recovery from acute kidney injury in two additional human cohort studies. In mice, bone marrow transplants from mice with mutations in TET2 or Jak2 demonstrated enhanced blood urea nitrogen and creatinine after ischemia reperfusion or urethral obstruction injuries with enhanced markers of inflammation and fibrosis attributed to macrophages that persisted chronically.

Take home message: Clonal hematopoiesis of indeterminate potential is a genetic mutation process associated with aging that yields macrophages that increase the risk of acute kidney injury and impaired recovery due to chronic inflammatory and fibrotic kidney changes. Therapeutic targeting of the inflammasome or downstream mediators of these genetic pathways may be a modifiable risk factor to limit progression to chronic kidney disease.