Vascular and inflammatory markers in chronic kidney disease

In patients with chronic kidney disease (CKD), inflammation and malnutrition are harmful and highly prevalent conditions with influence on the atherosclerotic process and outcome. The risk of cardiovascular disease (CVD) is substantially increased in CKD patients compared with healthy individuals. In uremic patients, homocysteine (Hcy) is a marker of disturbed metabolism and is suggested as a potential cardiovascular risk factor.

Several inflammatory markers are associated with cardiovascular morbidity and mortality. Together with CRP and serum amyloid P (SAP), pentraxin 3 (PTX3) is a protein belonging to the through evolution highly conserved pentraxin family and is involved in the regulation of the innate immune system. In contrast to CRP, which is synthesized in the liver, PTX3 is produced in the vasculature, and circulating levels mirror local inflammatory processes.

The aim of this thesis was to study inflammatory and metabolic biomarkers associated with cardiovascular risk in i) elderly individuals in the general population, ii) patients with CKD and iii) dialysis patients. We also investigated homocysteine and PTX3 as predictors of mortality in dialysis patients.

In paper I we measured the reduced, free and total forms of Hcy in plasma of patients with peritoneal and hemodialysis (HD) treatment and in patients with CKD stage 3 to 5. The more harmful form of Hcy, the reduced Hcy form (rHcy), was higher in all patients with impaired renal function than in healthy controls. In dialysis patients, the ratio of reduced and total Hcy (rHcy/tHcy) was higher than in CKD patients and the ratio further increased during HD treatment.

In paper II we investigated PTX3 and estimated glomerular filtration rate (eGFR) in two large community cohorts of elderly women and men in Uppsala. In a cross-sectional analysis, higher PTX3 levels were associated with lower GFR estimated from plasma cystatin C levels. In a longitudinal analysis, PTX3 independently predicted incidence of CKD as estimated by a drop of eGFR below 60 mL/min*1.73 m2 BSA.

These findings suggest that inflammatory processes are activated and play a role in the early stages of CKD. In paper III plasma levels of PTX3, CRP, albumin and Hcy were measured twice over a three-month period in HD patients. PTX3 had the highest intra-individual variation followed by albumin, CRP and Hcy. Furthermore, persistently elevated PTX3, increasing levels of CRP, decreasing levels of albumin and persistently low Hcy levels over three months were associated with a high mortality risk after adjustment for other risk factors.

In paper IV the release of PTX3 in response to inflammatory signals induced during a HD treatment was investigated. The plasma concentration of PTX3 was measured at the start and after 30, 60, 120, 180 and 240 minutes of the HD session. The increase of PTX3 was significant after 60 minutes, while CRP levels did not change during hemodialysis. We found that PTX3 is a sensitive marker of HD-induced inflammatory activity, probably because it is rapidly released from neutrophil granules on immune activation during HD.

In conclusion, accumulation of reduced Hcy in CKD and dialysis patients has potentially toxic effects on the vasculature. However, Hcy is not a reliable risk marker in patients with chronic kidney disease. PTX3 has a high intra-individual variation over three months, but the levels in CKD patients are associated with CVD and mortality. In elderly individuals in the community, PTX3 was associated with CKD incidence over a 5-year follow-up period. PTX3 is a quick and sensitive biomarker that has the potential to be an important clinical tool in patients with early and late stages of CKD, as well as in dialysis patients.

List of scientific papers

I. Sjöberg B, Anderstam B, Suliman M and Alvestrand A. Plasma reduced homocysteine and other aminothiol concentrations in patients with CKD, American Journal of Kidney Disease, 2006, Vol 47; No 1, 60-71.
https://doi.org/10.1053/j.ajkd.2005.09.032

II. Sjöberg B, Qureshi AR, Heimbürger, Stenvinkel P, Lind L, Larsson A, Bárány P and Ärnlöv J. Association between the inflammatory marker pentraxin 3, glomerular filtration rate and CKD incidence in two community-based cohorts, [Manuscript]

III. Sjöberg B, Snaedal S, Stenvinkel P, Qureshi AR, Heimbürger O and Bárány P. Three-month variation of plasma pentraxin 3 compared with C-reactive protein, albumin and homocysteine levels in haemodialysis patients. Clinical Kidney Journal 2014; 7: 373-379.
https://doi.org/10.1093/ckj/sfu071

IV. Sjöberg B, Qureshi AR, Anderstam B and Alvestrand A and Bárány P. Pentraxin 3, a sensitive early marker of hemodialysis-induced inflammation, Blood Purification 2012; 34: 290-297.
https://doi.org/10.1159/000342630