Clonal haematopoiesis, ageing and kidney disease

Abstract

Clonal haematopoiesis of indeterminate potential (CHIP) is a preclinical condition wherein a sizeable proportion of an individual's circulating blood cells are derived from a single mutated haematopoietic stem cell. CHIP occurs frequently with ageing - more than 10% of individuals over 65 years of age are affected - and is associated with an increased risk of disease across several organ systems and premature death. Emerging evidence suggests that CHIP has a role in kidney health, including associations with predisposition to acute kidney injury, impaired recovery from acute kidney injury and kidney function decline, both in the general population and among those with chronic kidney disease. Beyond its direct effect on the kidney, CHIP elevates the susceptibility of individuals to various conditions that can detrimentally affect the kidneys, including cardiovascular disease, obesity and insulin resistance, liver disease, gout, osteoporosis and certain autoimmune diseases. Aberrant pro-inflammatory signalling, telomere attrition and epigenetic ageing are potential causal pathophysiological pathways and mediators that underlie CHIP-related disease risk. Experimental animal models have shown that inhibition of inflammatory cytokine signalling can ameliorate many of the pathological effects of CHIP, and assessment of the efficacy and safety of this class of medications for human CHIP-associated pathology is ongoing.

Figure 1.. Subtypes of clonal haematopoiesis

a| With each cell division, haematopoietic stem and progenitor cells (HSPCs) can either self-renew, producing genetically identical HSPCs, or differentiate into daughter cells of the myeloid or lymphoid lineage. b| Haematopoiesis is normally polyclonal, wherein ~20,000 HSPCs contribute roughly equally to the circulating pool of daughter cells. Clonal hematopoiesis occurs when an HSPC acquires a genetic change that confers a proliferative advantage, leading to an overrepresentation of its progeny in the circulating pool of blood cells. c| Two major types of clonal haematopoiesis are recognized, defined by the type of genetic change that is driving clonality: CHIP (driven by point mutations or small indels in myeloid cancer-related genes) and mosaic chromosomal alterations (mCAs; driven by gains or losses of partial or whole chromosomes, or copy-neutral loss-of-heterozygosity). mCAs can further be subdivided into autosomal mCAs, mosaic loss of X (in genetic females) and mosaic loss of Y (in genetic males). d| The prevalence of each type of clonal haematopoiesis increases with age. Prevalence estimates for CHIP are approximated from ref. (variant allele fraction ≥ 2%). Prevalence estimates for autosomal mCAs are approximated from ref. (cell fraction ≥ 10%). Prevalence estimates for mLOX are approximated from ref. (cell fraction ≥ 5%). Prevalence estimates for mLOY based on ref.^,.

Figure 2.. The spectrum of clonal myeloid disease

Definitions of clonal hematopoiesis of indeterminate potential (CHIP), clonal cytopenia of uncertain significance (CCUS) as they compare to myeloid cancer. CHIP refers to a clonal blood cell population resulting from acquired mutations in myeloid malignancy-associated genes that is detected at a variant allele fraction (VAF) of ≥ 2%. When an individual with a CHIP mutation also has an otherwise unexplained cytopenia, this is referred to as a clonal cytopenia of undetermined significance (CCUS).

Figure 3.. CHIP mouse model systems.

a| The classic clonal hematopoiesis of indeterminate potential (CHIP) mouse model is based on transplantation of chimeric bone marrow — containing a fraction of haematopoietic stem and progenitor cells (HSPCs) with CHIP mutations and a fraction of cells without CHIP mutations — into mice that have undergone lethal irradiation of their bone marrow. Control mice typically receive a bone marrow transplant that consists entirely of non-mutated HSPCs. Recipient mice might have germline mutations and/or be exposed to dietary or other environmental exposures to model a phenotype of interest. b| The non-conditioned mouse model involves injecting CHIP-mutated HSPCs into mice that have not been irradiated. Engraftment and clonal expansion of HSPCs in the recipient bone marrow occurs over time. This radiation-sparing method is considered optimal for long-term experiments.

Figure 4.. Conceptual model of the role of CHIP in kidney health.

CHIP is an acquired inflammatory condition associated with acute kidney injury, progressive decline of kidney function, as well as several other conditions that can affect kidney health, including cardiovascular disease, gout, chronic liver disease, osteoporosis, obesity and insulin resistance. Mutagenesis of a myeloid cancer-associated gene is the initiating event in CHIP, and several risk factors for subsequent clonal expansion have been identified, including age, smoking, male sex, chronic inflammation, cytotoxic therapies and certain inherited genetic variants.