Proteins linked to atherosclerosis and cell proliferation are associated with the shrunken pore syndrome in heart failure patients

Abstract

Purpose:The "Shrunken pore syndrome" (SPS) is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFR cystatinC /eGFR creatinine -ratio. Studies have demonstrated a high risk for cardiovascular morbidity and mortality for patients with SPS. In this discovery study, we explored associations between SPS and proteins implicated in cardiovascular disease and inflammation in patients with heart failure. Experimental Design: Plasma samples from 300 individuals in HARVEST-Malmö trial hospitalized for the diagnosis of heart failure (mean age 74.9 ± 11.5 years; 30.0% female), were analyzed with a proximity extension assay consisting of 92 proteins. A Bonferroni-corrected p-value of 0.05/92 = 5.4 × 10 −4 was considered significant in the initial age and sex-adjusted analyses. Presence of SPS was defined as eGFR cystatinC ≤ 60% of eGFR creatinine .Results: SPS presented with significant associations (p < 5.4 × 10 −4 ) in age and sexadjusted logistic regressions with elevated levels of six proteins; scavenger receptor cysteine rich type 1 protein M130, tumor necrosis factor receptor 1, tumor necrosis factor receptor 2, osteoprotegerin, interleukin-2 receptor subunit alpha, and tyrosineprotein kinase receptor UFO. All proteins remained associated (p < 0.05) with SPS after multivariate adjustments. Conclusions and clinical relevance:In heart failure patients, SPS was associated with proteins linked to atherosclerosis and cell proliferation.

Impaired selective renal filtration captured by eGFRcysC/eGFRcrea ratio is associated with mortality in a population based cohort of older women

“…It is in stark contrast to a study by Purde et al in healthy Swiss seniors aged 60 and over (mean age 72), which reported a considerably lower prevalence (< 1%), although study participants may have been healthier than the general senior population 4 . It should also be noted that a lower eGFR cysC /eGFR crea ratio (CKD-EPI study equation) was reported in females than in males, a finding confirmed in a recent study linking SPS to female sex 11 . Given the considerably higher prevalence observed in the single sex, identically aged OPRA cohort it is clear that in terms of better understanding disruptions in the filtration process, age and comorbidities need to be taken into account.…”

“…The second of these questions is prevalence. Reported prevalence of SPS varies from 0.2 to 36%, but these estimates are primarily based on studies in selected patient cohorts, predominantly with heart disease 2 , 7 , 9 , 11 – 13 . The ratio of eGFR cysC /eGFR crea and hence prevalence in the general population is as yet unknown.…”

Glomerular filtration and shrunken pore syndrome in children and adults

“…[7] and [43] of, or being associated with, atherosclerosis. 7,43 A pivotal part of the pathophysiological process in SPS thus seems to be the accumulation of a large number of 5-30 kDa signalling proteins causing aberrations in several signalling pathways promoting the development of common disorders like cardiovascular disease, cancer and diabetes. Figure 1 displays this type of pathophysiological process.…”

Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk of a future first-ever myocardial infarction in women

“…Among subjects with heart failure, the Shrunken pore syndrome (SPS), defined as an eGFR cystatin C /eGFR creatinine ratio <0.6, has been associated with poor right ventricular systolic function [26], and with proteins involved in atherosclerosis [27]. In another study, SPS associated independently with higher mortality among patients undergoing elective coronary bypass grafting [28] and this was seen both in patients with low eGFR (<60 mL/min/1.73m 2 ) as well as in the group with normal eGFR (!60 mL/min/ 1.73m 2 ).…”

“…This association of early changes in glomerular function with MI and future surgery for aortic stenosis with concurrent coronary artery atherosclerosis was independent of apolipoproteins B/A1 ratio, diabetes, hypertension, BMI, and high sensitive CRP. The link with atherosclerosis is multifaceted, as shown by the association between the SPS and several proteins promoting atherosclerosis studied with a proteomic approach [27,29]. Calcification is a late stage in the complex process of atherosclerosis, and calcium metabolism may be disturbed in late-stage renal disease.…”