Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related state in which a hematopoietic stem cell suffers a mutation that gives it and its descendants replication advantages over their peers. Mutations of this nature spread throughout cell populations in an overlapping, layered way as they occur, a form of somatic mosaicism, but occurring in hematopoietic and immune cells. Like somatic mosaicism more generally, this has the look of a problem that should cause undesirable consequences. Drawing solid connections between CHIP and specific age-related diseases is a work in progress, however.
CHIP originated as the description of an early stage of dysfunction leading to leukemia, in that clonal expansion of potentially cancerous mutations in hematopoietic cells is observed. The connection to cancer is thus fairly robust. There is also less extensive evidence for CHIP to contribute to the progression of many age-related diseases via an increase in the chronic inflammation of aging. Much of the discussion to date has involved cardiovascular disease, but in today’s open access paper, researchers present evidence for CHIP to accelerate the progression of chronic kidney disease. In both of these cases, inflammation is the easy answer when it comes to questions about mechanisms, but that doesn’t mean it is definitely the case.
Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the clonal expansion of blood cells carrying somatic mutations in specific driver genes. An age-related disorder, CHIP is rare in the young but its prevalence increases rapidly in older adults, with at least 10{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} of individuals aged 65 and older affected. Recent studies have identified a causal role for CHIP in several chronic diseases of aging including atherosclerotic cardiovascular disease, heart failure, gout, liver fibrosis and cirrhosis, osteoporosis, and chronic obstructive pulmonary disorder (COPD).
CHIP is also recognized as a risk factor for acute kidney injury (AKI) severity and non-recovery. Mouse model evidence and human genetic studies point to inflammation as the key mediator of the CHIP-associated risk in each of these conditions. A hallmark feature of chronic kidney disease (CKD), chronic inflammation confers higher risks of kidney failure in CKD patients. CHIP has been associated with incident kidney function decline in the general population, though it is not clear whether the inflammatory burden of CHIP would meaningfully intensify the already-inflamed CKD state and affect clinical outcomes.
In this study, we first examined the prospective associations between CHIP and CKD progression events in four large CKD cohorts, totaling 6,216 individuals: the Chronic Renal Insufficiency Cohort (CRIC), the African American Study of Kidney Disease (AASK), subjects with CKD from the BioVU biorepository, and the Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT). We then used Mendelian randomization as an orthogonal method to assess the contribution of CHIP to estimated glomerular filtration rate (eGFR) decline. Finally, we evaluated the effect of experimental Tet2-CHIP on kidney function in a mouse model of CKD.
n the present work, we identify that non-DNMT3A CHIP is associated with a greater risk of kidney function decline in individuals with CKD, both when examining incident 50{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} eGFR decline or kidney failure events and annualized eGFR slopes. In Mendelian randomization analysis, a genetic predisposition for CHIP development was associated with a faster eGFR decline in those with CKD and diabetes. Additionally, in a Tet2-CHIP mouse model – the most common type of non-DNMT3A CHIP – dietary adenine administration led to more pronounced kidney functional impairment, inflammatory cell infiltration into kidney parenchyma, increased cytokine expression, and development of renal fibrosis when compared to mice without CHIP mutations fed the same diet. These findings are in line with our pilot study and with our work identifying non-DNMT3A CHIP as a risk factor for incident kidney function decline in the general population as well as for impaired recovery after AKI.