Innate immunity and cardiac structure in chronic kidney disease

Abstract

The inflammatory state of chronic kidney disease (CKD) leads to increased susceptibility to infections and cardiovascular complications. In this thesis we aimed to investigate development of inflammatory properties at different stages of CKD and changes in innate immunity as well as cardiac structure. Fibroblast growth factor 23 (FGF23), a phosphaturic hormone known to impact cardiovascular outcome and inflammatory markers in CKD was also analyzed.

In the first paper1 a cross sectional study of transmigrated monocytes in patients with advanced CKD was performed. Patients with CKD had an increased percentage of CD16+ monocytes, distorted TNF-α and IL-10 levels and a significantly higher level of fractalkine (CX3CL1). This inflammatory profile may in part mediate the altered immune response in CKD. The aim of the second paper2, was to investigate end organ damage to the heart of the pro-inflammatory state of CKD by evaluating cardiac structure and function in patients with CKD stages 2-5, compared with healthy controls in the PROGRESS cohort. Transthoracic echocardiography and Tissue Doppler Imaging (TDI) were performed to describe cardiac dimensions such as left ventricular mass, wall thickness and diastolic and systolic function. CKD patients had a higher prevalence of left ventricular hypertrophy (LVH) and alterations in systolic and diastolic myocardial function compared to the healthy controls.

In the third paper, inflammatory changes and altered monocyte function in patients with CKD stage 2-3 was compared to healthy controls in the PROGRESS cohort at baseline and at follow up after 3 and 5 years. Monocytes from CKD patients showed early functional abrasions, with altered adhesion molecule expression and significantly lower fMLP-induced upregulation of CD11b and decreased level of L-selectin (CD62L). CKD patients also had lower oxidative burst in response to fMLP over time as well as elevated pro-inflammatory cytokines; TNF-α, RANTES and IL-12. These findings suggest that a transformation of monocyte function occurs at an early phase of renal impairment and may together with increased plasma levels of pro-inflammatory cytokines contribute to the higher vulnerability of CKD patients to comorbidities.

Our primary objective of the fourth paper was to characterize the altered chemokine profile and leukocyte function at CKD stages 2-5 and investigate correlations between these markers and levels of FGF23. Elevated levels of FGF23 in CKD are associated to worse outcome and cardiovascular complications. FGF23 has also been described to interact in inflammatory processes. FGF23 was significantly elevated in the CKD group, and correlated to GFR, PTH, urinary albumin excretion (UAE) and phosphate as well as to the expression of IL-12 and RANTES. In vitro incubation of leukocytes with FGF23 reduced CD11b expression in resting as well as in fMLP-stimulated granulocytes. Together this indicates an influence of FGF23 on leukocyte transmigration and an interference with chemokine signaling in CKD.

In Summary; several factors are involved in inflammation in CKD. Better understanding of immunologic mechanisms and altered cellular function at different stages of CKD might help to explain the enhanced risk of cardiovascular disease as well as the increased susceptibility to infections. With improved knowledge of the inflammatory processes accompanying CKD we might obtain diagnostic and prognostic tools to improve clinical outcome.