Clonal haematopoiesis of indeterminate potential and impaired kidney function—A Danish general population study with 11 years follow‐up

Larsen, Morten Kranker; Skov, Vibe; Kjær, Lasse; Møller‐Palacino, Natascha A.; Pedersen, Rasmus Kristoffer; Andersen, Morten; Ottesen, Johnny T.; Cordua, Sabrina; Poulsen, Henrik Enghusen; Dahl, Morten; Knudsen, Trine Alma; Eickhardt-Dalbøge, Christina Schjellerup Schjellerup; Koschmieder, Steffen; Pedersen, Ken Steen; Çolak, Yunus; Bojesen, Stig E.; Nordestgaard, Børge G.; Stiehl, Thomas; Hasselbalch, Hans Carl; Ellervik, Christina

doi:10.1111/ejh.13845

Cited by 11 publications

(6 citation statements)

References 44 publications

(111 reference statements)

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“…Resolving whether this reflects differential biology versus lessened statistical power given that CH mutations in DNMT3A are more common than in other genes combined will require future studies. Indeed, some rarer hematopoietic mutations have also been associated with reduced renal function [37].…”

Section: Resultsmentioning

confidence: 99%

Impact of Clonal Hematopoiesis in COVID-19 Patients at High Risk for Adverse Clinical Outcomes

Smith,

Burugula,

Jones

et al. 2023

Preprint

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Purpose: Clonal hematopoiesis (CH) describes the aging-associated expansion of mutant hematopoietic cell populations. In various cohorts, CH has been associated with increased morbidity and mortality from non-hematologic diseases such as cardiovascular disease and infections, including COVID-19. Comorbidities placing individuals at risk of complications from these disorders, such as diabetes, also increase in prevalence with age and frequently co-exist with CH. How CH interacts with other aging-associated comorbidities to impact human health remains unknown. Methods: We assessed the impact of CH on the pre-existing end-organ damage and ultimate clinical outcomes among 242 patients hospitalized with COVID-19 at Michigan Medicine from March to June of 2020. In contrast to most previous studies, these patients skewed older with the majority having multiple comorbidities, which placed them at higher risk for end-organ damage and poor clinical outcomes. Results: Overall CH was not significantly associated with increased COVID-19 mortality after controlling for other risk factors, although we did note a borderline-significant association specifically for non-DNMT3A CH mutations. In contrast, we observed a significant association between CH and pre-existing chronic kidney disease (CKD), which was strongest for DNMT3A mutant CH. Conclusions: These data suggest that the clinical impact of CH is influenced by the specific gene(s) mutated and is further modified by other comorbidities and clinical risk factors frequently present in the elderly.

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Section: Resultsmentioning

confidence: 99%

Impact of Clonal Hematopoiesis in COVID-19 Patients at High Risk for Adverse Clinical Outcomes

Smith,

Burugula,

Jones

et al. 2023

Preprint

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“…Sixth, MPNs are associated with an increased risk of chronic kidney failure [55][56][57][58][59][60][61][62][63][64][65], which is considered to develop as a consequence of a chronic inflammatory state with ensuing renal impairment. It is intriguing to consider if "MPN-glomerulopathy" actually develops due to fibrogenesis in the kidneys as a consequence of the intramedullary release of growth factors-mitogenic for fibroblasts and endothelial proliferation (e.g., PDGF, TGGbeta, and VEGF).…”

Section: Reasons To Revisit Blood-based Extracellular Matrix Biomarke...mentioning

confidence: 99%

“…The importance of immune deregulation [35,36] with increasing T-cell exhaustion and tumor immune evasion consequent to defective tumor immune surveillance has been repeatedly underscored as one of the major mechanisms, contributing not only to MPN development and disease progression but also to the development of second cancers and their poorer survival as compared to the same cancers in the background population [30,31,34]. Highly intriguing, other inflammation-mediated comorbidities are also prevalent in MPNs, including much earlier development of drusen and age-related macular degeneration [37][38][39][40][41][42], increased risk of fractures, likely mediated by the chronic inflammatory state [43][44][45][46][47][48][49][50], chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease) [51][52][53][54], and chronic kidney disease [55][56][57][58][59][60][61][62][63][64][65]. Accordingly, patients with MPNs are not only at a constantly increased risk of major thrombosis in, e.g., the brain, heart, lungs, legs and abdominal arteries and veins [11][12][13][14][15] but also at an increased risk of being burdened by inflammation-mediated multimorbidities , including an increased risk of second cancers…”

Section: Introductionmentioning

confidence: 99%

Revisiting Circulating Extracellular Matrix Fragments as Disease Markers in Myelofibrosis and Related Neoplasms

Hasselbalch,

Junker,

Skov

et al. 2023

Cancers

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Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10–30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation—“a wound that never heals”—we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.

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“…Hence, such citizens are assumed to be in a pre-cancerous state, i.e., having CHIP. [12,18] Moreover, 38% of these are in a stable equilibrium CHIP state, 2.…”

Section: Introductionmentioning

confidence: 99%

“…CHIP is known to be associated with increased morbidity, such as coronary heart disease [21], chronic liver disease [22], chronic kidney disease [12,23], hematologic cancers [3,24], and potentially ulcerative colitis [25] and solid tumors [26]. From epidemiological studies, it is known that CHIP is overrepresented in cohorts with chronic inflammation, smoking [27][28][29], obesity [30,31], systemic lupus erythematosus [32], inflammatory cardiovascular diseases [33], and systemic sclerosis [34].…”

Section: Introductionmentioning

confidence: 99%

Aging, Inflammation, and Comorbidity in Cancers—A General In Silico Study Exemplified by Myeloproliferative Malignancies

Ottesen,

Andersen

2023

Cancers

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(1) Background: We consider dormant, pre-cancerous states prevented from developing into cancer by the immune system. Inflammatory morbidity may compromise the immune system and cause the pre-cancer to escape into an actual cancerous development. The immune deficiency described is general, but the results may vary across specific cancers due to different variances (2) Methods: We formulate a general conceptual model to perform rigorous in silico consequence analysis. Relevant existing data for myeloproliferative malignancies from the literature are used to calibrate the in silico computations. (3) Results and conclusions: The hypothesis suggests a common physiological origin for many clinical and epidemiological observations in relation to cancers in general. Examples are the observed age-dependent prevalence for hematopoietic cancers, a general mechanism-based explanation for why the risk of cancer increases with age, and how somatic mutations in general, and specifically seen in screenings of citizens, sometimes are non-increased or even decrease when followed over time. The conceptual model is used to characterize different groups of citizens and patients, describing different treatment responses and development scenarios.

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Clonal haematopoiesis of indeterminate potential and impaired kidney function—A Danish general population study with 11 years follow‐up

Abstract: The myeloproliferative neoplasms are associated with chronic kidney disease but whether clonal haematopoiesis of indeterminate potential (CHIP) is associated with impaired kidney function is unknown. In the Danish General Suburban Population

Cited by 11 publications

References 44 publications

Impact of Clonal Hematopoiesis in COVID-19 Patients at High Risk for Adverse Clinical Outcomes

Impact of Clonal Hematopoiesis in COVID-19 Patients at High Risk for Adverse Clinical Outcomes

Revisiting Circulating Extracellular Matrix Fragments as Disease Markers in Myelofibrosis and Related Neoplasms

Aging, Inflammation, and Comorbidity in Cancers—A General In Silico Study Exemplified by Myeloproliferative Malignancies

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